CN104902806B

CN104902806B - Neuropathological assessment system and method

Info

Publication number: CN104902806B
Application number: CN201380058415.8A
Authority: CN
Inventors: T·P·科勒曼; M·曼多扎; J·坦蒂昂罗克; R·吉尔达科斯塔; T·D·阿尔布莱特; G·斯通纳; R·方格
Original assignee: Salk Institute for Biological Studies; University of California San Diego UCSD
Current assignee: Salk Institute for Biological Studies; University of California San Diego UCSD
Priority date: 2012-11-10
Filing date: 2013-11-11
Publication date: 2019-06-04
Anticipated expiration: 2033-11-11
Also published as: EP2916721A1; KR102273684B1; CA2888355A1; CA2888355C; US20150305686A1; EP2916721A4; KR20150082322A; US10258291B2; JP2016501056A; BR112015010624A2; WO2014075029A1; CN104902806A

Abstract

Methods, systems, and devices for assessing susceptibility to, disease progression, and treatment of neuropathological aspects are disclosed. In one aspect, a method for providing an assessment related to a neurological or neuropsychiatric disorder comprises: selecting a profile category indicative of one or more aspects of cognitive or sensory function associated with a neurological or neuropsychiatric disorder, presenting a sequence of stimuli to the subject, wherein the sequence of stimuli is based on the selected profile category, acquiring physiological signals of the subject before, during, and after the presentation of the sequence of stimuli to produce physiological data, and processing the physiological data to generate an information set comprising one or more quantitative values associated with the selected profile category.

Description

The assessment system and method for europathology

Cross reference to related applications

Patent document requires " METHOD AND APPARATUS FOR submitting, entitled on November 10th, 2012 EVALUATION OF VULNERABILITY AND/OR PROGRESSIVEPATHOLOGY OF NEUROPSYCHIATRIC DISORDERS IN HUMANS AND FOR ASSESSMENTOF POTENTIAL THERAPEUTIC PHARMACOLOGICAL AGENTS FOR NEUROPSYCHIATRICDISORDERS IN NON-HUMAN PRIMATE The priority of the U.S. Provisional Patent Application No.61/724,969 of BIOLOGICAL MODELS ".The full text of above-mentioned patent application It is incorporated herein by reference, a part of the disclosure as patent document.

Technical field

Patent document is related to system, equipment and process for analyzing brain function.

Background technique

Electroencephalogram (EEG) is the electrical activity shown by brain obtained using the electrode on the scalp for being positioned at object Record forms the spectral content of the nerve signal oscillation comprising EEG data collection.For example, the brain detected by EEG technology Electrical activity can include as such as voltage fluctuation caused by the ionic current in the neuron of brain.In some contexts, EEG Refer to the record of spontaneous electrical activity of the brain in a bit of time (for example, less than 1 hour).EEG can be used in clinic Diagnostic application, including epilepsy, stupor, encephalopathy, brain death and other diseases and defect, or even for sleep and sleep disturbance Research.In some cases, diagnosing tumour, cerebral apoplexy and other focal brain disorders that EEG has been used for.

One example of EEG technology includes the record of event related potential (ERP), the record refer to EEG record with The relevant brain response of given event (for example, simple stimulation and complicated process).For example, ERP include with feel, move and/ Or cognition handles relevant electroencephalographic response --- brain wave.ERP and perception (for example, vision, sense of hearing etc.) and cognition are (for example, note Meaning, language, decision etc.) brain measure association.For example, ERP equally can be in the assessment of nervous system or neuropsychiatric disorders Be used as objective metric in monitoring.Typical ERP waveform includes the time-evolution of positive and negative voltage deviation (referred to as component).Example Such as, typical component is using the component because of letter (N/P: positive/negative) and number (instruction the prolonging from stimulation event of its appearance Late, unit is millisecond) classify.

Summary of the invention

The invention discloses for acquire and characterized using physiologic information (for example, brain signal) object nervous system or The system, apparatus and method of the treatment of the pathology and/or vulnerability and/or the such disease of assessment of neuropsychiatric disorders.

In an aspect, the method for providing assessment relevant to nervous system or neuropsychiatric disorders includes: choosing Select the anatomy of the one or more aspects of instruction and nervous system or the associated cognition of neuropsychiatric disorders or sensory function (profile) classification；(present) stimulus sequence is presented to object, wherein the stimulus sequence is based on selected anatomy classification；? Before presenting the stimulus sequence, during and after acquisition target physiological signal to generate physiological data；And handle physiology number The information collection comprising one or more quantitative values with selected anatomy category associations is generated accordingly.

In another aspect, for assessing the method packet of the curative effect of the treatment to nervous system or neuropsychiatric disorders It includes: selection instruction and the associated cognition of nervous system or neuropsychiatric disorders or the anatomy of the one or more aspects of sensory function Classification；Stimulus sequence is presented for the object of the treatment of nervous system or neuropsychiatric disorders to positive experience, wherein the stimulation sequence Column are based on selected anatomy classification；Before presenting the stimulus sequence, during and after acquisition target physiological signal to generate Physiological data, and physiological data is handled to generate the letter comprising one or more quantitative values with selected anatomy category associations Curative effect of the breath collection instruction to the treatment of object.

In another aspect, the system for assessing nervous system or neuropsychiatric disorders includes: for generate to pair As the stimulation sending device for the stimulus sequence presented, wherein the stimulation includes vision, the sense of hearing, smell, tactile or taste stimulation matchmaker At least one of be situated between；It is connect with object interface to detect before and after, during presenting the stimulus sequence and be shown by object The sensor device of physiological signal out, wherein the stimulus sequence is based on indicating associated with nervous system or neuropsychiatric disorders The cognition of the one or more aspects of cognition or sensory function-feeling dissects classification；And data processing system, the data processing System is communicated with sensor device, and is configured to comprising one or more storage units and is configured to processing as life The physiological signal of data is managed to generate one of the information collection comprising one or more quantitative values with selected anatomy category associations A or multiple processors, wherein the one or more quantitative values include the pathology for describing nervous system or neuropsychiatric disorders Rank quantitative score.

In some implementations, presently disclosed technology can be with the associated electricity of brain activity for acquisition including using Special physiological signal (for example, the electroencephalogram and/or electromyogram) acquisition technique of physiologic readout and have it is special stimulation be in The equipment for sending structure (for example, the stimulations such as vision, the sense of hearing, somatesthesia, tactile, sense of taste), and including using special analysis skill Art (e.g., including signal processing, basis and high-level data statistics and sorting algorithm) providing to individual and/or Group they with the interested associated vulnerability of nervous system or neuropsychiatric disorders and/or progressive pathology side The assessment in face, and in some implementations, nervous system or neuropsychiatric disorders are controlled to provide using animal model Treat the assessment of the curative effect of (for example, therapeutic agent).

Theme described in patent document can be can provide the specific sides of one or more features in following features Formula is realized.For example, method disclosed herein, system and equipment, which provide, to be allowed to the more accurate, more objectively and more of the mankind Quickly additional diagnosis and pathology assessment, and allow to enhance to the basis as nervous system or neuropsychiatric disorders The tool of the pharmacological research (for example, effective way of open advanced drug research) of neuromechanism.For example, skill disclosed herein Art allows user to draw, measurement and analysis and interested nervous system or neuropsychiatric disorders (for example, schizophrenia, Alzheimer disease etc.) associated specific brain mark (marker), and be therefore provided with put into row venereal disease reason, vulnerability with And the potential curative effect of therapeutic agent and the purposive information of efficiency.Moreover, for example, the implementation of presently disclosed technology Advanced special knowledge is not needed to operate, and just because of this, can be accessed by extensive potential user, for example, to expert and Both naive users effectively provide reliable, accurate and information-based result.

Detailed description of the invention

Figure 1A shows the acquisition for physiological signal, analysis and assessment to generate individual or group cognition to object And/or perceptual evaluation is (for example, the progress or easily ill of europathology of the instruction including the influence of specific drug induccd brain Property) presently disclosed technology an exemplary system schematic diagram.

Figure 1B -1D is shown for generating exemplary cognitive and/or feeling the illustrative methods of the quantitative information collection dissected Procedure chart.

Fig. 1 E and 1F show the block diagram of the exemplary frontal electrode biosensor equipment of presently disclosed technology.

Fig. 1 G show nervous system or neuropsychiatric disorders for characterizing object pathology and/or vulnerability and/ Or the schematic diagram of another exemplary system of the presently disclosed technology of the treatment of the such disease of assessment.

Fig. 2 shows the data of the mismatch negative ERP for the mark for being shown as schizoid progressive pathology songs Line chart.

Fig. 3 shows the data graphs for being shown as the P300ERP of mark of schizoid vulnerability.

Fig. 4 shows the schematic diagram of exemplary intensity (decibel level) the oddball mode for showing auditory stimulation and presenting.

Fig. 5 shows the exemplary pretreatment and analytic process of the computer implemented method of illustrative custom design Flow chart.

Fig. 6 shows an example of the pseudocode of the exemplary program analytic process of presently disclosed technology.

Fig. 7 shows one of the graphic user interface (GUI) of the exemplary program analytic process of presently disclosed technology Example.

Fig. 8 A and 8B show exemplary come what is carried out using the exemplary data sets of the mismatch negative ERP of human subjects The data graphs of the result of ERP processing and analysis.

Fig. 9 A and 9B are shown using the exemplary data sets of the P300ERP of human subjects at the exemplary ERP carried out The data graphs of reason and the result of analysis.

Figure 10 shows the example of liability or progressive pathology for monitoring psychoneural and/or nervous system disorders The procedure chart of property user procedures.

Figure 11 shows the non-human primate EEG cap in illustrative 22 channel of presently disclosed technology.

Figure 12 A and 12B show the mismatch using non-human primate object in the case where no physiologic therapy Property negative wave ERP exemplary data sets come the data graphs of the result of the exemplary ERP processing and analysis that carry out.

Figure 13 A and 13B are shown using non-human primate object in the case where no physiologic therapy The exemplary data sets of P300ERP are come the data graphs of the result of the exemplary ERP processing and analysis that carry out.

Figure 14 A and 14B show negative using the mismatch of the non-human primate object under different physiologic therapies The exemplary data sets of wave ERP are come the data graphs of the result of the exemplary ERP processing and analysis that carry out.

Figure 15 A and 15B show the P300ERP's for using the non-human primate object under different physiologic therapies Exemplary data sets are come the data graphs of the result of the exemplary ERP processing and analysis that carry out.

Figure 16 shows the curative effect for assessing the treatment pharmacological agent for nervous system or neuropsychiatric disorders The procedure chart of example user process.

Figure 17 shows the modules shown for integrating variety classes, subclass and function, and them to be made to join together work to create Build for stimulate present, exemplary " full-enclosed " of the user-friendly automated system of data signal sampling and processing application system The schematic diagram of the general architecture of system.

Specific embodiment

According to American National mental hygiene research institute, neuropsychiatric disorders will continue to influence US adult population about 46.4%, about 22.3% in these cases be listed in it is serious.These neuropsychiatric disorders include attention deficit hyperactivity disorder (ADHD), Alzheimer disease, schizophrenia, depression, dementia and bipolar disorder etc..Although thousands of Research in the snagged feature of being permitted in these obstacles is described, but for the neural basal and correlation of its cause of disease Social dissemination still lack common recognition and understanding.Moreover, although in vulnerability assessment, diagnosis and certain psychoneurals barrier Certain clinical methods are introduced in the treatment hindered, however, there remains diagnosis, assessment and treatment technology is developed, so that providing makes Accuracy, simplification, and just for user (for example, physician/clinician, researcher and ordinary populace) guidance The ability of true action scheme.

For example, in ADHD, using the behavior evaluation of the one or more classifications belonged in following classification to many individuals It is screened, for example it is to be noted that power is not concentrated, is mostly dynamic and inflammable.Just because of this, meet a large amount of children and adult of these standards It would generally start drug therapy and behaviour therapy, this may result in the expensive treatment of several years.For example, having perhaps in these drugs It is mostly incitantia, these incitantias can reduce the behavior of ADHD symptom due to unknown cause still to be proved, to the greatest extent Manage they can normal health cause in vivo overacfivity/behavior that is stimulated.But the use of these drugs Possibly this obstacle can not be cured, it is also possible to bring undesirable psychological side effect.For example, the increase of ADHD illness rate is (for example, beauty The children of state 9.5%) have been attributed to better diagnostic techniques and high misdiagnosis rate, for example, high misdiagnosis rate may be due to The subjectivity of behavior evaluation.No matter which kind of situation, be only that the behavior evaluation of usually subjectivity is insufficient as ADHD The independent measurement instrument of diagnosis and ADHD drug therapy.

As the substitution of unilateral act measurement, additional composite measurement, for example, physiological measurements, can be used in psychoneural Liability assessment, diagnosis and the therapeutic process of obstacle.For example, by doing so, research circle and medical field better understood when The reason of neuropsychiatric disorders and mechanism, it may for example comprise ADHD, and therefore reinforce their research, the monitorings of exploitation more efficiently And the ability of the route of applied treatment.Presently disclosed technology is capable of providing for using objective metric and assesses object The vulnerability and pathology of psychoneural are simultaneously created for pharmacological research and the new analysis method of exploitation to mediate (mediate) And/or cure the technology of these obstacles.

Disclosed herein is the nervous systems for acquiring and characterizing using physiologic information (for example, brain signal) object Or the system, apparatus and method of the treatment of the pathology and/or vulnerability and/or the such disease of assessment of neuropsychiatric disorders.

In some implementations, presently disclosed technology can be with the associated electricity of brain activity for acquisition including using Special physiological signal (for example, the electroencephalogram and/or electromyogram) acquisition technique of physiologic readout and have it is special stimulation be in The equipment for sending structure (for example, the stimulations such as vision, the sense of hearing, smell, somatesthesia, tactile, sense of taste), and including using special point Analysis technology (e.g., including signal processing, basis and high-level data statistics and sorting algorithm) provide to individual And/or group they with the interested associated vulnerability of neuropsychiatric disorders and/or progressive pathology in terms of Assessment, and in some implementations, it is provided using non-human primate model and the potential of neuropsychiatric disorders is controlled Treat the assessment of the curative effect of drug.

For example, in some implementations, presently disclosed technology be capable of providing for stimulate present, data acquisition, this Full-enclosed (all-inclusive) system of the automation of ground and/or long-range data process&analysis and the output of user's result System.Such system can be used to reduce or eliminate and electrophysiological recording and the associated complication of analytical technology (complications), thus for user (e.g., including (but being not limited to) clinician, pharmaceuticals researcher and general consumption Person) provide for evaluator (or other animals) nervous system or neuropsychiatric disorders pathology and/or vulnerability and The non-invasive quick diagnosis instruments of inspection of the curative effect of the treatment (e.g., including potential therapeutic agent) of such disease.

In an aspect, presently disclosed technology includes relevant to nervous system or neuropsychiatric disorders for providing The method of assessment.This method includes the one of selection instruction and nervous system or the associated cognition of neuropsychiatric disorders or sensory function A or many aspects anatomy classifications.This method includes that stimulus sequence is presented to object, and wherein the stimulus sequence is based on selected Dissect classification.This method include before presenting the stimulus sequence, during and after acquisition target physiological signal to generate life Manage data.This method includes handling physiological data to generate and include and the selected one or more quantitative values for dissecting category associations Information collection.For example, the quantitative values of information collection generated include for describing being susceptible to suffer from for nervous system or neuropsychiatric disorders The quantitative score of property or the rank of progressive pathology.For example, selected anatomy classification can indicate to influence cognition or sensory function One or more aspects various nervous systems or one of neuropsychiatric disorders or a variety of, it may for example comprise it is (but unlimited In) attention, memory, learning ability, imaginary characteristic, figure integration ability, semantic integration ability, target acquisition ability, feelings Thread valence, preference or state of consciousness.Neuropsychiatric disorders and nervous system disorders and/or neurodegenerative disease are able to use herein Disclosed technology is assessed and is characterized.Such neuropsychiatric disorders and nervous system disorders and/or neurodegenerative disease Example includes but is not limited to such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Alzheimer Disease, dementia, depression, bipolar disorder, schizophrenia, epilepsy, multiple sclerosis (MS), Parkinson's disease and Huntingdon Disease.In addition, for example, this method can be implemented to provide instruction with nervous system disorders and dysfunction it is associated cognition or The qualitative assessment of the one or more aspects of sensory function, the obstacle include but is not limited to stroke, aphasia, and Tang Shi is comprehensive Disease, palate heart face (enlightening George (DiGeorge)) syndrome, stupor, long-term or acute use or drink, and show brain signal Indicate other nervous system disorders and dysfunction of the variation of (for example, ERP).

In certain implementations of the method for providing assessment relevant to nervous system or neuropsychiatric disorders, example Such as, the physiological data processing carried out to generate information collection can include: based on the stimulation and selected anatomy classification presented Come identify with the associated time interval of physiological signal, physiological data corresponding with time interval is grouped as one or more packets Data set, and provide between packet data collection or within relationship statistical measures for selected anatomy classification generation one A or multiple quantitative values.In some instances, the association of preassignment classification or continued stimulus based on individual stimulation is capable of in grouping In relationship at least one of determine.In its of the method for providing assessment relevant to nervous system or neuropsychiatric disorders In his implementation, for example, the physiological data processing carried out to generate information collection can include: based on the stimulation presented and Selected anatomy classification come identify with the associated time interval of physiological signal, physiological data corresponding with time interval is grouped as One or more packets data set, and provided using the physiological data before collected from the object or other objects Between packet data collection or within relationship statistical measures to generate one or more quantitative values for selected anatomy classification. And in other implementations of the method for providing assessment relevant to nervous system or neuropsychiatric disorders, for example, The physiological data processing carried out to generate information collection can include: to be known based on the stimulation and selected anatomy classification presented Not with the associated time interval of physiological signal, physiological data corresponding with time interval is grouped as one or more initial packets Data set, using be related to the statistics control of initial packet data collection to each of the stimulus sequence presented to object stimulate into Row classification, is grouped as one or more packets data for physiological data corresponding with time interval based on the stimulation classified again Collection, and provide between packet data collection or within relationship statistical measures with for selected anatomy classification generation one or Multiple quantitative values.

In certain implementations of the method for providing assessment relevant to nervous system or neuropsychiatric disorders, example Such as, this method can also include: and integrate to form improved stimulus sequence as object using information generated, and this is improved Stimulus sequence is presented to object.In addition, for example, this method can also include: before the presenting of improved stimulus sequence, period The physiological signal of acquisition target is later to generate new physiological data, and handles new physiological data to generate and include and choosing The augmentation information collection of the quantitative values of one or more augmentation of fixed anatomy category associations.In certain implementations of this method In, acquisition is not related to the behavior reaction of object, and handling not includes processing behavioral data to generate information collection.However at it In his implementation, for example, this method can also include: the acquisition target before and after, during the presenting of stimulus sequence Behavior signal to generate behavioral data, and behavioral data handled together with physiological data with generate comprising with it is selected Dissect the information collection of one or more quantitative values of category associations.

In another aspect, presently disclosed technology includes controlling for assessing nervous system or neuropsychiatric disorders The method of the curative effect for the treatment of.This method includes selection instruction and nervous system or the associated cognition of neuropsychiatric disorders or sensory function One or more aspects anatomy classification.This method includes the treatment to positive experience for nervous system or neuropsychiatric disorders Object present stimulus sequence, wherein the stimulus sequence is based on selected anatomy classification.This method, which is included in, presents the stimulation sequence Before column, during and after acquisition target physiological signal to generate physiological data.This method includes processing physiological data with life At the information collection with one or more quantitative values of selected anatomy category associations of the curative effect comprising indicating the treatment to object. For example, the quantitative values of information collection generated include the nervous system or psychoneural barrier for describing the object of positive experience treatment The quantitative score of the Pathological degree hindered.For example, be used to treatment object therapy (e.g., including in the side for assessing its curative effect Treatment before and during the implementation of method) it can include that pharmacological agent, electro-shock therapy, cognitive rehabilitation treatment or operation are controlled It treats.

For example, pharmacological agent (for example, combination drug or compound) can be used in extensive nervous system or nerve It treats, restores in phrenoblabia, mitigate or improve pathological symptom.The implementation of this method can be used in pharmacological research, example Such as, symptom induced drug and disease are assessed by assessing the modulation of collected relevant physiological and/or behavior signal from object Shape restores the effect of both drugs.For example, electro-shock therapy (ECT) is interventional therapy, which is included in positive experience ECT Apply electric current in the object for the treatment of (for example, in psychoneural patient) to induce epilepsy, the mode (example alleviated as offer Such as, in some cases in depression and schizophrenia).For example, cognitive rehabilitation treatment (CRT) is Behavioral training agreement It uses, the method as the recovery for promoting impression and/or cognitive defect.CRT includes behavior stimulation, and causing to be asserted can increase Into the nerve of the recovery of the defect of various phrenoblabias (for example, schizophrenia, ADHD, aphasia, depression etc.) Training and starting.The example of CRT treatment can include that enhancing treatment is treated or recognized to cognition correcting, and wherein Behavioral training can be by Computer (machine system) guidance (and/or assessment).For example, CRT treatment can be by making the physiology of CRT agreement Yu object oneself It is associated with behavior measurement in conjunction with presently disclosed technology and implements so that process and result automation and optimization.In addition, for example, CRT treatment can equally be implemented together with the treatment based on pharmacological agent.For example, the curative effect of operative treatment is come using this method Assessment, for example, will acquire the physiological measurements (for example, EEG) of brain response in the method, is performed simultaneously surgical intervention, this is outer Section intervenes the mode that can be used to the state of monitoring patient and detect the stimulation of specific brain area and the reaction of intervention effect, Mode as more preferable guided operation.

In the implementation of this method, for example, object can include human subjects and non-human subject.For example, inhuman Class object can include primate, Suidae object and Muridae object etc..In some implementations, for example, this method also It can include that the pharmacological agent of given dose is injected or is fed into object.For assessing nervous system or psychoneural In certain implementations of the method for the curative effect of the treatment of obstacle, for example, the physiological data processing carried out to generate information collection Can include: identified based on the stimulation and selected anatomy classification presented with the associated time interval of physiological signal, will be with The corresponding physiological data of time interval is grouped as one or more packets data set, and provide between packet data collection or it The statistical measures of interior relationship are to generate one or more quantitative values for selected anatomy classification.In some instances, it is grouped energy Enough determined based at least one in the incidence relation of the preassignment classification of individual stimulation or continued stimulus.For assessing mind In other implementations of the method for the curative effect for the treatment of through system or neuropsychiatric disorders, for example, for generate information collection and into Capable physiological data processing can include: to be associated with to identify with physiological signal based on the stimulation and selected anatomy classification presented Time interval, physiological data corresponding with time interval is grouped as one or more packets data set, and use from this On object or other objects it is collected before physiological data come provide between packet data collection or within relationship system Meter measurement thinks that selected anatomy classification generates one or more quantitative values.

In certain implementations of the method for the curative effect of the treatment for assessing nervous system or neuropsychiatric disorders, example Such as, this method can also include: and integrate to form improved stimulus sequence as object using information generated, and this is improved Stimulus sequence is presented to object.In addition, for example, this method can also include: before the presenting of improved stimulus sequence, period The physiological signal of acquisition target is later to generate new physiological data, and handles new physiological data to generate and include and choosing The augmentation information collection of the quantitative values of one or more augmentation of fixed anatomy category associations.In certain implementations of this method In, acquisition is not related to the behavior reaction of object, and handling does not include processing behavioral data to generate information collection.However In other implementations, for example, this method can also include: the acquisition target before and after, during the presenting of stimulus sequence Behavior signal to generate behavioral data, and behavioral data handled to generate together with physiological data and includes and selected Anatomy category associations one or more quantitative values information collection.

In another aspect, disclosed technology includes the system for assessing nervous system or neuropsychiatric disorders. The system include for generating the stimulation sending device of the stimulus sequence presented to object, wherein the stimulation include vision, the sense of hearing, At least one of smell, tactile or taste stimulation medium.The system includes to be connect with object interface to present the stimulation sequence The sensor device of the physiological signal shown by object is detected before and after, during column, wherein the stimulus sequence is based on referring to Show that cognition-feeling of the one or more aspects with the associated cognition of nervous system or neuropsychiatric disorders or sensory function dissects Classification.The system includes the data processing system communicated with sensor device, which is configured to comprising one Or multiple storage units and the physiological signal for being configured to handle as physiological data include and selected anatomy class to generate The one or more processors of the information collection of not associated one or more quantitative values, wherein the one or more quantitative values include Quantitative score for the nervous system of rendered object or the rank of the liability of neuropsychiatric disorders or progressive pathology.

In certain implementations of the system, for example, data processing system can include: being located near sensor device And it communicates with to receive the local computer of the detected physiological signal from sensor device, wherein local computer It is configured for carrying out the preliminary treatment of detected physiological signal to generate initial physiological signal data；And long-range meter Calculation machine receives the initial physiological signal number from local computer via communication network or link and local computer communications According to and handle initial physiological signal data to generate and include and cognition-feeling dissects one or more quantitative values of category associations Information collection.For example, local computer can communicate with stimulation sending device and be configured for selected anatomy classification To determine the stimulus sequence to present to object.For example, local computer can be configured for receiving and information generated The data for collecting associated or therefrom obtaining, and object progress individual character is directed to for modifying the stimulus sequence to object to generate The stimulus sequence of the modification of change.For example, stimulation sending device can include display screen for generating image sequence and/or be used for Generate the loudspeaker of sound sequence.For example, stimulation sending device can include for generating in smell, tactile or taste stimulation The driver of the stimulus sequence of at least one stimulation.

In certain implementations of the system, for example, object can be undergoing for nervous system or psychoneural Inspection of the treatment (for example, pharmacological agent treatment, ECT treatment, CRT treatment or operative treatment) of obstacle in the physiological signal of object During survey.For example, data processing system can be configured for processing physiological data with generate include and selected anatomy classification The information collection of associated one or more quantitative values, is used to indicate the curative effect of the treatment to object.For example, data processing system quilt It is configured to generate machine program based on information collection generated, wherein machine program can drive another equipment or system To manage the treatment obtained from the information being contained in information collection generated.In some instances, machine program can be used To inject the pharmacological agent or ECT electro photoluminescence of given dose in real time during the implementation of assessment.

The exemplary embodiment of system, apparatus and method disclosed herein

Figure 1A shows the acquisition for physiological signal, analysis and assessment and is used to indicate with generating for example including specific medicine The individual or group cognition and/or perceptual evaluation of the object of the progress or vulnerability of europathology including the influence of source property brain Presently disclosed technology exemplary modular system 100 schematic diagram.For example, system 100 can be implemented to only make It is provided with physiological data collected from object (for example, apparent behavior reaction not from object) and nervous system Or the associated cognition of neuropsychiatric disorders and/or feeling dissect.However, system 100 can be implemented in other implementations It is provided for using behavioral data from object or both physiology and behavioral data and nervous system or psychoneural barrier Associated cognition and/or feeling is hindered to dissect.In some implementations, system 100 can be implemented to acquire before use To physiology from the object or other objects (for example, population data) and/or behavioral data come provide with nervous system or The associated cognition of neuropsychiatric disorders and/or feeling dissect.

As shown in Figure 1A, system 100 is configured for independent in a variety of different embodiments comprising that can be configured at Modular unit or equipment.System 100 include for configure specific stimulation present structure 102 realize stimulation to object or Module 101 is presented in the stimulation of stimulus sequence presented.In some instances, stimulation presents module 101 to include such as processor It is realized with the calculating equipment including storage unit.For example, stimulation can include any stimulus type, including vision, the sense of hearing, smell Feel, tactile or taste stimulation medium.Structure 102 is presented in specific stimulation can be configured to include (but being not limited to) one kind or more Interval between duration that kind certain types of stimulation, stimulation are presented, stimulation, the multiplicating (if present) each presented, With the magnitude and/or frequency parameter (for example, the intensity of sound or the brightness of light or contrast level) of the type association of stimulation, With every kind stimulate present associated numeral flag, and the label or classification (for example, targeting or non-targeted) of stimulation.

System 100 can present module 101 with stimulation and communicate to object comprising presenting structure 102 based on such as stimulation It presents stimulation or module 103 occurs for the stimulation of stimulus sequence.For example, module 103, which occurs, for stimulation can include visual displays, listen At least one of loudspeaker and driver are felt, for providing smell, tactile and/or taste stimulation.In some implementations, For example, module 101 is presented in stimulation and stimulation occurs module 103 and can be configured in same equipment, for example, computer or shifting Dynamic communication and/or calculating equipment.

System 100 includes physiology and/or behavioral data acquisition module 110, for the progress of module 103 to occur via stimulation Stimulation or the presenting of stimulus sequence before, during and/or after acquisition target physiological signal and/or behavior signal.For example, Physiology and/or behavioral data acquisition module 110 can include but is not limited to electroencephalogram (EEG) system, electrocardiogram (ECG) system System, electromyogram (EMG) system, electrochemical sensing system and eye tracking system etc..In some implementations, for example, physiology And/or behavioral data acquisition module 110 can include with signal collecting device (for example, the analog or digital being coupled to the memory Amplifier) coupling biosensor, for example, EEG, ECG, EMG, electrochemistry or other kinds of sensor device.For example, raw It manages and/or behavioral data acquisition module 110 can be configured in the EEG system of the standard with rigid electrode or use can It is worn in the portable EEG system of the flexible electronic devices on object.For example, physiology and/or behavioral data acquisition module 110 The EMG system or use that the standard with rigid electrode can be configured in can be worn on can for example detect on object With in the portable EMG system of sleepiness or the flexible electronic devices of the associated movement of facial expression.

System 100 includes to locate in advance for receiving the analysis of physiological signal collected and/or behavior signal as data Module 111 is managed, and in some implementations, which executes pretreatment point to data collected Analysis technology.Show for example, analysis preprocessing module 111 can be implemented to the identification in physiological data (for example, EEG data) The morbidity mark of example property, is segmented physiological data, filters original signal data to increase signal-to-noise ratio etc..In certain realization sides In formula, for example, analysis pretreatment 111 can be realized in the example for realizing physiology and/or behavioral data acquisition module 110 In the computer equipment of property equipment or system communication.In some implementations, for example, analysis pretreatment 111 can be configured In same example devices or system for realizing physiology and/or behavioral data acquisition module 110.

System 100 includes for handling physiology and/or behavioral data to provide object or group's (in some instances) The anatomy generation module 115 of cognition or perceptual evaluation.For example, dissecting generation module 115 handles physiology and/or behavioral data with life At the information collection 117 comprising one or more quantitative values with selected anatomy category associations, for example, being used for the mind of rendered object The rank of liability or progressive pathology through system or neuropsychiatric disorders or for describing the treatment for obstacle The score (for example, the score can be specific to the object and its situation) of curative effect.

Figure 1B shows for generating and by for example dissecting the same nervous system or psychoneural barrier that generation module 115 is realized Hinder the procedure chart of the illustrative methods 170 of the information collection of relevant selected anatomy category associations.Method 170 can include being used for It is identified between physiological signal and/or behavior signal data associated time based on the stimulation and selected anatomy classification presented Every process 171.For example, time interval can include connected, intermittent, continuous, discrete or single time point.Side Method 170 can include for data (for example, physiology and/or behavior) corresponding with time interval to be grouped as one or more points The process 172 of group data set.For example, process 172 can include preassignment classification and/or continued stimulus based on individual stimulation Incidence relation is grouped physiology and/or behavioral data.Method 170 can include for providing between packet data collection The statistical measures of relationship within or are with the process 173 for the selected one or more quantitative values of anatomy classification generation.Certain In implementation, for example, method 170 can include for enhancing the signal of physiology and/or behavioral data in packet data collection Process.

Fig. 1 C show for use before individual and/or community information come generate with by for example dissecting generation module The illustrative methods of the information collection of the 115 same nervous systems realized or the relevant selected anatomy category associations of neuropsychiatric disorders 180 procedure chart.Method 180 can include believing for being identified based on the stimulation and selected anatomy classification presented with physiology Number and/or the associated time interval of behavior signal data process 181.Method 180 can include for will be with time interval pair The data (for example, physiology and/or behavior) answered are grouped as the process 182 of one or more packets data set.For example, process 182 It can include based on the incidence relation of the preassignment classification of individual stimulation and/or continued stimulus come to physiology and/or behavioral data It is grouped.Method 180 can include for use from the object and/or other objects (e.g., including one or more groups Body) on it is collected before physiological data and/or behavioral data come provide between packet data collection or within relationship Statistical measures are with the process 182 for the selected one or more quantitative values of anatomy classification generation.

Fig. 1 D shows for using guidance sorting technique the same mind for generating with being realized by for example dissecting generation module 115 The procedure chart of the illustrative methods 190 of information collection through the relevant selected anatomy category associations of system or neuropsychiatric disorders. Method 190 can include for being identified and physiological signal and/or behavior based on the stimulation and selected anatomy classification presented The process 191 of the associated time interval of signal data.Method 190 can include for will data (example corresponding with time interval Such as, physiology and/or behavior) it is grouped as the process 192 of one or more initial packet data collection.Method 190 can include being used for Classified using the statistics control for being related to initial packet data collection to each stimulation in the stimulus sequence presented to object Process 193.Method 190 can include for will physiology corresponding with time interval and/or behavior based on the stimulation classified Data are grouped as the process 194 of one or more packets data set again.Method 190 can include for providing in packet data Between collection or within relationship statistical measures to generate the processes 195 of one or more quantitative values for selected anatomys classification.

In some instances, guidance sorting algorithm can be realized with context-specific parameter by dissecting generation module 115, For instructing and being selected in various classification and statistical method, it may for example comprise the technology of (but being not limited to) based on ANOVA 116a, the technology 116b based on support vector machines and minimum description length technology 116c etc..In some implementations, it dissects Generation module 115 can be realized in computer system or comprising one or more remote computation processing equipments (for example, cloud Server) communication network (referred to as " cloud ") on.

System 100 includes for improving cognition generated relevant to nervous system or neuropsychiatric disorders and/or sense Feel brain-computer interface module 120 dissecting and/or for starting the interaction between user and machine.In an example, brain machine Interface module 120 can be based on (just examined individual subject, individual subject examined before are generated via dissecting The object group that module 115 is assessed) generated dissect 117 present mould to provide new stimulation or multiple stimulations to stimulation The feedback of block 101 transmits, it may for example comprise provides in the ongoing implementation process of system 100.For example, brain-computer interface mould Block 120 can adaptively change or be analyzed processing so that desired target designed for optimally extracting from object The stimulus modality of maximized information.For example, brain-computer interface module can be generated based on information collection generated for can For driving another equipment or system (for example, equipment or system) to manage from the information being contained in information collection generated In the machine program for the treatment of that obtains.For example, certain implementations of brain-computer interface module 120 can be including but not limited to auxiliary Habit of giving financial aid to students and target detection application.

In certain implementations of system 100, generation module 115 is dissected, module 101 is presented in stimulation, mould occurs for stimulation Block 103 and brain-computer interface module 120 (and in some cases, there are also data acquisition modules 110) can be realized in single meter In calculation system, for example, desktop computer, laptop computer or the mobile communication including smart phone or tablet computer Equipment.In other implementations, module 115,101,103 and 120 can be configured in being in communication with each other and include module 115, in two or more calculating equipment of 101,103 and 120 various combinations.

In some implementations, system 100 can be configured as only comprising physiology and/or behavioral data acquisition module 110 and dissect generation module 115, for generates indicate nervous system or neuropsychiatric disorders progress or vulnerability and/or The cognition of the object for the treatment for the obstacle that he/her is undergoing and/or perceptual evaluation.In such exemplary realization side In formula, system 100 is able to use ring, and currently obtainable border is stimulated (for example, light, sound, smell, taste around object And/or tactile).In such an example, system 100 can be implemented in single calculating equipment, for example, in the calculating In equipment, module 110 is configured for receiving the behavior reaction and/or recording said physiological data of object via the input of equipment.

" SYSTEMS AND METHODS FOR SENSORY AND submitting, entitled on September 27th, 2013 System and method disclosed herein are provided in the PCT Patent Application PCT/US13/62491 of COGNITIVE PROFILING " Other examples, the patent application are incorporated by herein, a part of the disclosure as patent document.

In certain implementations of presently disclosed technology, physiological data collection module 110 can include portable biography Sensor equipment, the portable sensor devices include that front is placed in electrophysiologicalsignal signal detection electrode on the forehead of object most Excellent configuration, for providing for example with the liability or pathological evolution of the nervous system of object or neuropsychiatric disorders or to the barrier The relevant cognition of the curative effect of the treatment hindered and/or perceptual evaluation.It is submitting, entitled on October 14th, 2013 “CONFIGURATION AND SPATIAL PLACEMENT OF FRONTAL ELECTRODE SENSORS TO DETECT Certain examples of such system are provided in the PCT Patent Application PCT/US13/64892 of PHYSIOLOGICAL SIGNALS ", The patent application is incorporated by herein, a part of the disclosure as patent document.

In some instances, the illustrative portable electric biosensor equipment of presently disclosed technology can include position In the forehead EEG signal recording electrode not Chong Die with hair on the forehead of object, for being mostly used, quick and not lofty Physiological data collection (e.g., including brain signal monitoring).For example, in some implementations, illustrative biosensor is set It is standby to be configured as small size, and can be with a variety of different materials (for example, these materials can add for specific application Work) it is formed, allow these equipment to be easy to be applied, seldom perhaps even without being felt by user or by others See.For example, the application and operation of such equipment can for example be executed according to simple instruction by user, it is special technology is not needed Length is to apply or operate the equipment.This can alleviate the problems of existing system significantly, including need technical expertise Operation and sensor device lack comfort and portability.

Fig. 1 E shows the frontal electrode sensor that can acquire the electricity physiological signal in forehead area on the head from object The block diagram of the exemplary embodiment of equipment 160.Equipment 160 includes the substrate 161 of electrically insulating material, which sets certain It can be made of mechanical flexibility material in standby implementation.In some instances, substrate 161 can include dimethyl silicone polymer (PDMS), the thin polyurethane with acrylic acid adhesive or polyvinyl alcohol (PVA) etc..Frontal electrode sensor device 160 It include recording electrode 162, reference electrode 163 including three-electrode configuration, and between recording electrode 162 and reference electrode 163 The grounding electrode 164 being configured on the basal plane (for example, detection faces with the skin contact of user of equipment 160) of substrate 161.If Standby 160 electrode is configured in forehead area along sagittal direction, so that recording electrode 162 is located at behind grounding electrode 164, it should Grounding electrode 164 is located at behind reference electrode 163.Grounding electrode 164 is at least partially situated at recording electrode on substrate 161 Between 162 and reference electrode 163.The forehead area on this head in user or record-ground connection-reference electrode cloth on prefrontal area Office can be such that total area occupied of the electrode of frontal electrode sensor device 160 minimizes, and be for such sensor device It is significant beneficial.This record-ground connection-reference electrode layout also provides the good letter between recording electrode and reference electrode Number isolation, so that more sensitive and high quality signal be allowed to record operation.Electrode in sagittal direction rather than with sagittal side Aligned in general in vertical horizontal direction is the notable feature of this record-ground connection-reference electrode layout, and can be Beneficial sensing operation is provided in terms of acquiring the various cognitions/psychological condition signal with desired precision.

In some embodiments of equipment 160, for example, recording electrode 162, grounding electrode 164 and reference electrode 163 are by line Property is arranged on substrate 161.For example, the layout of these three electrodes can be aligned to substantially along sagittal direction and recording electrode Straight line.In the other embodiments of equipment 160, for example, these three electrodes can arrange according to nonlinear queue, the queue Including being located at the subsequent recording electrode 162 of grounding electrode 164, which is located at behind reference electrode 163, is grounded Electrode 164 is at least partially disposed between recording electrode 162 and reference electrode 163 on substrate 161.

Frontal electrode sensor device 160 can be used to the electric physiological data of acquisition with circuit electric coupling.In Figure 1A institute In the exemplary embodiment shown, frontal electrode sensor device 160 includes being electrically interconnected respectively via individual on substrate 161 The circuit 169 of 165a, 165b and 165c and 164 electric coupling of recording electrode 162, reference electrode 163 and grounding electrode.In certain realities Apply in example, for example, circuit 169 can include respectively via such as electrically conductive conduits 165a, 165b and 165c and each electrode 162, The transmitter unit of 163 and 164 telecommunications.In the present embodiment, the life that equipment 160 is able to record physiological signal and will be recorded Reason signal is transferred to long-range electric signal processing unit (for example, amplifier) and/or computer system.In addition, for example, circuit 169 can include the power module with transmitter unit electric coupling, for providing electrical power to transmitter unit.

In certain embodiments, for example, as shown in Figure 1B, frontal electrode sensor device 160 can be comprising respectively and mutually Even thermal interface (contact) gasket 166a, 166b and 166c of 165a, 165b and 165c coupling, for providing conductive surface so that External circuit is electrically connected with the electrode 162,163 of equipment 160 and 164 interfaces.For example, external circuit can be Electric signal processing list First (for example, signal amplifier) and/or computer system.

For example, record, reference and ground signalling collected are received by signal processing unit, which is used for Signal collected is handled in difference amplifier to amplify the difference of the physiological signal of recording voltage and reference voltage.By equipment The ground signalling of 160 (via grounding electrode 164) records can be connected to the Grounding of exemplary differential amplifier, for example, For the synchronization signal parameter between equipment 160 and amplifier.For example, can make may be via record system for grounding electrode 164 The leakage current for flowing through object minimizes, and thereby reduces any artefact.For example, with circuit (for example, external circuit) electric coupling Grounding electrode 164 require no connection to the ground wire of circuit.The replaceable role of grounding electrode can include being used as actively Eliminate the electrode of interference.For example, grounding electrode is capable of being electrically connected to " right leg drive " feed circuit, for example, the feed circuit exists Make in some bio signal amplification systems of electric signal (for example, EEG, EMG, ECG) for measuring the very little issued by body With.For example, frontal electrode sensor device 160 can acquire the reference count in the electricity physiological signal in forehead area.Reference electrode 163 position and its relative record electrode 162 are (alternatively, in some implementations, there are also it other than recording electrode 162 His recording electrode) spacing be important because interested reading will be opposite by the activity recorded by recording electrode 162 It is determined in the movable comparison that is recorded by reference electrode 163.For example, if such signal be it is identical, it is detected Signal reading will be 0.From this view, for example, can be positioned at recording electrode 162 will allow to interested life The place detected of reason signal, and reference electrode 163 is positioned at will not acquire interested physiological signal and (or show Gone out the significant decaying of interested signal) place, far from recording electrode 162 sizable distance at.But when Keep area occupied (for example, by entire electrod-array the space occupied region or real estate) of the equipment 160 on forehead minimum When change becomes important, this present bigger challenges.For example, in example shown in figure 1A and 1B, electrode 162,163 and 164 It positions and is spaced apart according to the mode for making signal collected dramatically different, and be thus relevant, and occupy by electricity The minimum gross area that pole 162,163 and 164 occupies.Described in patent document for determining the optimal of position and spacing The method of configuration is complicated, and can integrate psychologic, neuro-physiology and engineering principle.In Figure 1A and 1B institute In the example shown, the position of reference electrode 163 is positioned relative to recording electrode 162 at the queue of substantially straight line, and In this example, both electrodes 162 and 163 and grounding electrode 164 are equally arranged in the central median sagittal by forehead area On line.It is provided as physiological data by the signal of signal processing, which is then able to be processed to provide cognition And/or feel to dissect.

In some implementations, it is raw can be configured to the epidermis electronics directly worn on the skin for equipment 160 Reason sensor device or the wearable items contacted with forehead area.In some implementations, for example, equipment 160 can wrap It is attached to include the one or more being for example configured on the top surface (for example, the not non-detection face with the skin contact of user) of equipment 160 The electric insulation layer added.Extra play further can provide support to equipment 160.In some instances, extra play can include each Kind Art Design, so that equipment 160 equally can be used as (temporarily) tatooing when being directly worn on its skin by user.

In the frame of method disclosed herein, it can be realized in the application in the computer system of presently disclosed technology Program can be configured such that the user (for example, operator of system) of application by the application with client (for example, stimulation is in Send and data acquisition program) it interacts, which can be presented to user via graphic user interface (GUI).It is applying Certain implementations in, program can indicate user how by EEG recording electrode be placed on the head of object with simplify record Process, it may for example comprise be used for the placement of complete EEG cap (for example, using rigid electrode) or the sensing based on frontal electrode The instruction of the placement of device equipment (for example, using flexible electronic devices).For example, between computer implemented application and user Such interaction can accelerate overall process, and prevent potential problem from occurring, for example, between multiple electrodes channel " crosstalk ".

Fig. 1 G show nervous system or neuropsychiatric disorders for characterizing object pathology and/or vulnerability and/ Or the schematic diagram of the system 150 of the treatment of the such disease of assessment.For example, system 150 can be used to implement illustratively to apply Program.System 150 include stimulation for being interacted with object and operator present with data acquisition computer 151, and via Physiological signal recording equipment 155 (for example, equipment 160 or recording equipment based on rigid electrode) collects the physiology from object Signal data.It presents with the input in data acquisition computer 151 for example, operator is capable of providing stimulation to start to object Assessment (e.g., including vulnerability and/or progressive pathology assessment for nervous system or neuropsychiatric disorders are controlled Treat curative effect evaluation).System 150 includes can be relative to the data processing computer 152 that computer 151 is local computer (simultaneously And be for example same computer with 151 in some instances) or computer 152 can be via such as internet with for example The remote computer or computer system network that computer 151 communicates.For example, data processing computer 152 is configured for It handles collected physiological data and generates the liability or progressive pathology for describing nervous system or neuropsychiatric disorders Rank and/or for the obstacle treatment curative effect assessment.For example, assessment generated can be to user (for example, operation Member and/or object) it the stimulation that can be used as being realized by computer 151 is provided presents information with the input of data acquisition program Collection.In some implementations, operator can present in starting stimulation and present and number with before data acquisition in stimulation The anatomy classification of operator is presented to via such as GUI according to selection on collecting computer 151.As shown in Figure 1 G, mould is presented in stimulation Block and data acquisition module can be configured in computer 151, concurrently to run and mutually convey information, for example, association The timing for adjusting stimulation to occur.Sensory stimuli (for example, the sense of hearing and/or vision etc.) can be presented by computer 151 to object, simultaneously Physiological signal (for example, EEG) is recorded.It can allow for such as user that can select to stimulate by the application program that system 150 is implemented Present mode, data acquisition equipment and signal processing technology.

For dissecting the method disclosed herein of europathology and obstacle and the example implementations of system

It there is described herein the object (or group) of the one or more aspects for providing instruction cognition or sensory function The example implementations of the system and method disclosed herein of cognition and/or perceptual evaluation, for example, these system and method energy It is enough in the diagnosis or assessment or the treatment to the obstacle of the liability and pathological evolution of nervous system or neuropsychiatric disorders The assessment of the curative effect of (for example, drug development).Object includes the mankind and non-human primate.

In described example, specific stimulation collection is presented while recording the EEG signal from object to obtain Interested event related potential and relevant neural hunting of frequency.The example used in illustrative implementation Property ERP includes but is not limited to P300 and MisMatch Negativity.It can be implemented to provide example using presently disclosed technology Property other exemplary ERP for dissecting of cognition-feeling include but is not limited to N400, and recognize with feeling/concept of reward Know the associated ERP reaction of processing.Cognition disclosed herein and/or feeling, which dissect generation method and system, can be used to measurement object Brain mark, and in addition also assess the information and convert thereof into for being characterized in nervous system or neuropsychiatric disorders The vulnerability of object or the purposive data of progressive pathology, and the assessment for thus providing obstacle dissects.For example, with it is non- People's primate model using in relevant application, illustrative implementation is included under multiple physiologic therapy/situations The electrophysiologicalmeasurements measurements of execution, the electrophysiologicalmeasurements measurements be capable of forming for the functional of nervous system and neuropsychiatric disorders and The basis of available animal model, it may for example comprise schizophrenia and Alzheimer disease etc..

Schizophrenia be influence about 1% population neuropsychiatric disorders, this 1% population is about 300 in the U.S. Ten thousand people.Schizophrenia can disintegrate with such as illusion, bigoted, thinking, emotional poverty and the symptom for executing function difference etc close Connection.Conventional diagnosis and pathology assessment program is based on observed behavior and the experience reported.For example, patient can report Accuse the symptom of such as sense of hearing illusion, vain hope and suicidal thoughts etc.As in other neuropsychiatric disorders, although clinical Observation and self-report can be beneficial, but there is still a need for for diagnosing and the more objective method of pathology assessment.For example, smart The specific example of refreshing obstacle, such as schizophrenia may may also will not show its many conventional diseases in diagnosis Shape, but may show some time afterwards, this further adds the complexity of diagnosis process.

Some have argued that obstacle may be at least partly by γ-aminobutyric acid (GABA) and glutamic acid neurotransmitter system Caused by dysfunction.For example, it was found that N- methyl-D-aspartate (NMDA) receptor antagonist of acute Subanesthetic dose Agent ketamine can induce typical consciousness, cognition and neurologically handicapped in the defect that schizophrenia occurs.It is several anti- Antipsychotic drugs were just produced for treating the neuropsychiatric disorders from the 1950s, many in these drugs All target these specific neurotransmitter systems.But most of drug is not sufficient to handle obstacle itself and its symptom, and It can be related to unfavorable side effect, for example, recognizing blunt, dyskinesia (unconscious somatic movement) or agranulocytosis (low white blood cell count(WBC)).In addition, for example, current second generation antipsychotics has been found at them to chronic psychiatric There is huge limitation, and aobvious with conventional first generation drug in terms of validity in terms of the validity of the patient of Split disease It writes different.

Pharmacological research and patient care (e.g., including diagnosis, vulnerability assessment and the monitoring of progressive pathology) two Aspect currently lack reliably and effectively new paragon by appreciable brain mark (being obtained from brain physiology) with it is felt emerging The neuropsychiatric disorders of interest associate, to establish the more objective correlation for surpassing behavior evaluation.For example, suffering from A Er The patient of Ci Haimo disease and in schizoid patient, mismatch negative ERP (is closed with echoic memory and variance detection Connection) amplitude can weaken, for example, defect of the instruction in terms of recognizing update, and thereby show the memory trace of cognitive decline, shortening Mark duration and/or affected auditory discrimination power.In addition, for example, by Alzheimer disease those of influenced object with The incubation period that the object of health compares the reduced amplitude and increase that can show P300ERP is (associated with the adjusting of attention Brain mark).

Mismatch negative

Mismatch negative (MMN) is ERP modulation, and ERP modulation is the function feeling note in the level of sense of hearing sensory cortex Recall the automatic preceding attention index of processing.MMN can be drawn by the sense of hearing and visual stimulus.MMN is believed to reflection and pierces to deviation Sharp preceding attention detection, and capable of being calculated, in " oddball " mode as to deviation (for example, seldom occurring ) reaction of stimulation with to the difference wave between the reacting of standard (for example, frequent) stimulation.For example, MMN is usually pierced in deviation 100~250ms after excitation is raw occurs, and maximum voltage is on the EEG scalp location in forehead and center.MMN can be by Figure violate substantially and (give fixed spacing/frequency figure for example, violating by the stimulation for presenting greater or lesser spacing) with And more abstract deviation is (for example, violate " staged " and presenting the spacing equal or smaller with the spacing of previous stimulation The figure of frequency) the two extraction.

MMN can be related to extensive nervous system and neuropsychiatric disorders.For example, to including such as schizophrenia The scientific research of the patient of various phrenoblabias including disease, Alzheimer disease and autism spectrum disorder (ASD) has been The report of system ground: these patients illustrate the ability that the detection of decline newly stimulates compared with health objects.With this behavioral deficiency Unanimously, the amplitude of MMN reduces, and thereby MMN can be considered as the progressive pathology of these obstacles or the mark of vulnerability.

For example, schizophreniac, which usually shows, lacks MMN generation, processing and cognition update aspect are paid attention to before showing Obstacle.MMN is utilized as the mark of schizoid progressive pathology.Fig. 2 shows have to use single electrode (Cz) carry out Healthy People (healthy patient) (collator (controls)) with the MMN's of schizophreniac The data graphs of the example results of comparative studies, the curve graph show that MMN is substantially reduced in schizophreniac. For example, the measured value of MMN can provide schizoid progressive cognitive decline after the onset to physician/clinician Reliable biological marker allows them to diagnose patient and more accurately with the propagation of the graph representation obstacle.

P300

The feature of P300 can be the forward direction electricity that there is the distribution of center-top maximum scalp to be 300~800ms Reaction.The subjective probability of happening inversely related of P300 and article.For example, P300 is applied in sensation target Detection task, In the sensation target Detection task, target has drawn the P300 of more high amplitude compared with other articles.

P300 is the event related potential that can be drawn by the sense of hearing and visual stimulus, usually in oddball mode.Although It reflects the index of deviation stimulation, and as MMN, but P300 is stimulated it certainly by indicating that attention is transferred to deviation Oneself distinguishes with MMN.Stimulation importance is indexed by it as a result, and its stimulation that is relevant for task and/or paying attention to It is the largest.The amplitude of P300 is usually the largest on the center of inside and top EEG scalp location, and is pierced in deviation Occur between about 300ms and 1000ms after excitation is raw.For example, P300 reaction be substantially reduced with include pay attention to and Various neuropsychiatric disorders (for example, Alzheimer disease and schizophrenia etc.) including cognition update defect are associated, with The P300 amplitude of normal healthy controls person, which is compared, has lesser P300 amplitude.Moreover, for example, it has been shown that lacking in P300 generation It falls into and is present in high-risk person, these high-risk persons can be defined as the individual of the relative with the obstacle.

It includes that young Healthy People and old Healthy People are (right that Fig. 3, which is shown with what is carried out using single electrode (Cz), According to person) including various subject populations P300 with schizoid high-risk, just falling ill and chronic patient The data graphs of the example results of the comparative studies of P300, the curve graph show that P300 is aobvious in schizophreniac It writes and reduces.It is with schizophrenia family history but do not have also clinically impacted for example, as shown in the data graphs of Fig. 3 Personal (such as, it is considered to be " high-risk " patient) equally show the P300 amplitude of reduction.Moreover, data graphs disclose The different gradients of P300 amplitude, the risk or existing pathology between the crowd studied are very related.Presently disclosed technology energy It is enough used to refer to the individual neurological disorder of (or group) and/or the liability of pathology (for example, schizophrenia), this can permit Individual obtain earlier and/or may be preventative treatment/therapy, for example, such treatment/therapy and being proved to if it exists It is effective.

I. in human subjects for neuropsychiatric disorders liability and progressive pathology assessment MMN and The example implementations of P300ERP

I.1. example sexual stimulus presents structure

5 adult male objects (for example, the age is 20~36 years old) for assessing neuropsychiatric disorders liability and/ Or it is evaluated in the example implementations of the presently disclosed technology of pathological evolution.

It includes passive sense of hearing intensity oddball mode that structure is presented in illustrative stimulation, for presenting not to human subjects With the tone of intensity, these human subjects are each sitting in segregate rather dark room in implementation process.For example, listening Feel that stimulation includes the low-intensity of 100ms (for example, 10ms rise/fall) or the pure sinusoid tone (for example, 1500Hz) of high intensity. Frequently 80% and 20% time is presented in (standard) and infrequent (deviation) stimulation respectively, as shown in Figure 4.Fig. 4 is shown The schematic diagram of exemplary intensity (decibel level) oddball mode for presenting for auditory stimulation is shown.Interval between stimulation For 700ms.For example, presenting 1200 standard stimulus and 300 deviation stimulations in each illustrative recording conversation.For example, Two kinds of situations of high deviation (for example, substandard) and low deviation (for example, high standard) are used, for example, for allowing different To the comparison of the reaction of identical stimulation (for example, low or high) under background (for example, standard or deviation).

The illustrative stimulation presented for being used to control stimulation in this example presents mode and uses Cogent 2000 Programming.For example, the other software packet being able to use includes but is not limited to Psychtoolbox, E-Prime, Presentation And Qt.Tone is presented to human subjects using loudspeaker.Illustrative human subjects are required maintenance center fixation, for example, So that motion artifacts minimize.For example, fixation target is presented using apart from 21 inches of the CRT monitor of object 40cm Red circle (for example, diameter is 1 degree) on a dark background.Target occurs before beginning is presented in auditory stimulation, and is remembering The entire period of record session remains visible.For example, two methods be used to create illustrative red center fixation point and The rectangular stimulation of blue.For the illustrative fixation point, for example, computer implemented process is (for example, use MATLAB script Creation) background image of the creation highly with the black that width is 350 pixels is used to (for example, red gun is equal to 0；Green rifle Equal to 0；0) blue rifle is equal to.Then, illustrative script runs nested For circulation using round normal equation, with logical It crosses and the red gun of image is changed into 255, changing into 0 and blue rifle is changed into 0 for radius green rifle is that 7 pixels are long Pixel within degree changes red.For the illustrative rectangular stimulation of blue, imaging software be used to creation having a size of 157 × The image of 157 pixels, red gun are equal to 0, and green rifle is equal to 0, and blue rifle is equal to 255.Illustrative red center is solid Viewpoint is used to the helpful object in entire recording conversation and maintains fixation.

Illustrative computer implemented process is used to configuration display, 2000 journal file of Cogent, parallel port And sound card.Then, illustrative computer implemented process is used to pierce auditory stimulation (for example, bass and high pitch) and vision Swash (for example, fixation point and blue are rectangular) to be loaded into core buffer.For example, this shows in order to create biggish deviation perception The process of example property discontinuously presents the stimulation of two or more deviations.For example, this includes " 1 " and " 2 " by creation Array presents sequence to realize.For example, " 1 " expression standard stimulus, and " 2 " indicate deviation stimulation.In certain realization sides In formula, for example, abovementioned steps can execute before stimulation is presented, to reduce calculated load and to increase delay precision.

For example, presented For circulation (the exemplary MATLAB script of illustrative computer implemented process, For generating fixation target) in, fixation point is presented and to be maintained as object in entire block visible.Then, the circulation along It presents sequence and repeats.When it encounters " 1 ", illustrative computer implemented process will be first by event flag/trigger It is sent to physiological data collection system (for example, EEG logger computer), followed by standard stimulus is (for example, for situation 1 is bass；For situation 2 be high pitch) present.Similarly, when it encounters " 2 ", illustrative computer implemented process Event flag/trigger will be sent to illustrative EEG logger computer first, followed by deviation stimulation (for example, It is high pitch for situation 1；For situation 2 be bass) present.Which kind of stimulation event flag/trigger points out (for example, low Or high) presented.For example, after following each auditory stimulation closely being interval (ISI) between stimulation for 700ms.For example, In the illustrative implementation, fixation target is only used for the auxiliary for helping to minimize eye movement, and just because of this, Fixation is not quantized.

I.2. illustrative EEG data collection/record

In some implementations, for example, traditional EEG system with rigid electrode is used to acquisition brain wave.For example, EEG scalp reading is acquired with using the Vision Recorder software of BrainAmpMR system.The EEG cap in 64 channels BrainCap MR is used together with AgCl electrode, and the collection for human subjects data is (for example, for having 5k resistor The PCB ribbon cable of BrainCap-MR；BrainCap MR Box 1.2；With 1.5mm electric shock-prevention safety socket terminal and The sintering ring electrode of the heavy lead of 120cm).

Human subjects, which are sitting in, to be recorded on indoor chair, and is started electroencephalogram and attached the names of pre-determined candidates process.For example, the process be related to by EEG cap is placed on the head of object and fixes it with plastics chin straps.In some instances, used diameter be 56cm or The cap of 58cm, the estimation size based on object header.Then, the electrode gel of Signa uses under each electrode of cap Side is injected at curvilinear plastic injector, to create conducting bridge between the scalp of object in electronics itself.We are same Sample is massaged (massage) gel using wooden cotton swab (Q-tips) and establishes stronger conductance will pass through reduction impedance.This Outside, for example, wooden cotton swab, which is used to massage gel, establishes stronger conductance will pass through reduction impedance.For example, this technology Use the impedance rank of each electrode including such as grounding electrode and reference electrode is reduced to < 5k Ω.

Before starting illustrative implementation using EEG record, object, which is sitting in, presents monitor and audio tweeter Before, and it is required to be maintained at vision fixation during entire implement on illustrative red center fixation point and as far as possible Ground limits their athletic performance to prevent motion artifacts in neuro-physiological data.For example, giving object to emphasize these points Show the online record of their original brain wave, this can show in their frequent blinkings to them and/or sting always under oneself Bar when data what can occur.Finally, for example, the lamp of recording room is fully closed, window is hidden not before coming into effect Light leakage, and crack is sealed against the light entrance of outside.

I.3. illustrative EEG data analysis

Illustrative EEG data is analyzed using software Analyzer 2.0.In the illustrative implementation, to next It is similarly analyzed from the sum of the mankind from the data of monkey.For example, analysis program includes making first from original record The data set of reference quotes identical rear pillow part channel again, as different plant species (for example, people: Oz, O1, O2, PO7, PO8, P7,P8；Macaque: Oz, O1, O2, P3, P4) between new comparable reference.This is followed by bandpass filtering (for example, low cutoff frequency Rate: 0.1Hz, higher cutoff frequency: 50Hz) and sample rate is changed into from 1000Hz by 250Hz based on spline interpolation.For example, In order to avoid derived from the analysis artefact of the difference of sample size, illustrative data set is first relative to deviation mark position (example Such as, originating: -1000ms terminates: 600ms) be segmented so that it will will include whole deviation tests (for example, N=300) and The only code test directly before deviation (for example, N=300).Then, for example, generated analysis time-histories (epochs) It is segmented relative to deviation mark position or standard sign position (for example, starting: -200ms terminates: 600ms), to know Not relevant deviation and standard analysis time-histories.For both standard and deviation analysis time-histories, baseline correction (for example, Starting: -200ms terminates: 0ms) it is applied, multiple features artefact excludes tool and is applied (for example, being applied to whole channels；It is maximum Allow voltage step: 50 μ V/ms；Maximum allowable interval value difference: 200 μ V；Minimum allowable interval activity: 0.5 μ V).ERP (mean value) Then it is calculated for each channel and situation (for example, high standard, substandard, high deviation and low deviation).For example, difference wave (for example, deviation subtracts standard) for two kinds of situations (for example, low deviation subtracts substandard and high deviation subtracts high standard) into Row calculates, and then low and high difference wave is averaged to obtain MMN component, and for the low reaction and height of deviation Reaction is averaged to obtain P3 component.

I.4. the identification of mankind ERP

In the illustrative implementation, illustrative MMN component and P3ERP component use in the mankind to be established Using identical test mode, (for example, oddball mode, MMN is the difference that deviation stimulation subtracts standard stimulus in this mode Wave, and P3 is observed in deviation irritant test) criterion to identify, and determine timing, electrode position for these ERP components It sets, voltage scalp is distributed and neural generators.For example, after identifying MMN, in average ERP wave near peak amplitude Establish the when window of 40ms.Window is used to extract the peak amplitude values of each object from single test when this is illustrative.Example Such as, these values are then used to that (for example, factor 1: standard is to deviation in two-way duplicate measurements ANOVA；Factor 2: height is to low) in Statistical analysis.P3 component is studied in the average response to low deviation and high deviation.Similarly, for example, identifying P3 After component, establish 40 milliseconds of when window near peak amplitude in ERP wave, and this when window be used to from single test Extract average amplitude value.For example, the statistical significance of P3 reaction is examined using t to calculate.

I.5. it is analyzed using the exemplary EEG data of the program of custom design

Calculated in addition to using existing software package (for example, BrainVision Analyzer 2.0) MMN component and Except P300 component, illustrative implementation further includes the computer implemented analytic process using illustrative custom design (for example, with MATLAB Script Programming) determines MMN component and P300 component to handle MMN and P300 data, to create ERP waveform.The computer implemented program of illustrative custom design can be implemented to automatic data processing (for example, holding Row signal processing step, for example, filtering, channel removal, resampling etc.), MMN difference wave ERP is calculated, P300ERP is calculated, and And statistical analysis is executed to data-oriented, it is all that the mouse being guided several times is all only needed to click.For example, using existing technology, Typical ERP pretreatment and time needed for analysis can be a few hours to several weeks.The program of illustrative custom design can It is implemented to interior processing data (for example, illustrated below) at average about 2-3 minutes.Although illustrative code uses MATLAB is developed, but its specific frame and analytic process can be realized with other programming languages, it may for example comprise (but not It is limited to) C++ and Java.Moreover, its frame does not depend on used in the implementation of examples described herein Illustrative brain mark (for example, MMN and P300), but can be applied to other brain marks, it may for example comprise (but being not limited to) N400, there are also handling with feeling/concept cognition of reward, associated ERP reacts and additional brain signal is (for example, nerve Hunting of frequency).In addition, the adaptability of the program of illustrative custom design can allow for it to be applied on multiple platforms.For example, Illustrative computer implemented method can in local runtime (for example, on knee or desktop computer of user) or Long-range operation is (for example, can be via including the mutual of one or more long-range calculating treatmenting equipments (for example, the server in cloud) In the computer system or communication network for networking (referred to as " cloud ") to access).In the following example, computer implemented method Using such as MATLAB, because of its user-friendly programmed environment and the built-in function for handling big data matrix.

Fig. 5 shows the exemplary pretreatment and analytic process of the computer implemented program of illustrative custom design 500 flow chart.As previously mentioned, for example, the process is unlike the prior art to be fully automated, to help User draws and measures reliable brain mark, and accelerates the process, this can be beneficial to diagnosis and/or pathology assessment significantly And therapeutic agent exploitation.Moreover, this illustrative automation process can allow for only seldom or remember without electro physiology The individual for recording the special knowledge of technical aspect benefits from presently disclosed technology and will be imposed in themselves work.

Pretreatment includes that operator's selection is allowed to be ready to use in the data set that the nervous physiology of object is assessed with analytic process 500 (for example, by exemplary data collection module illustratively stimulation presentation process in from object collected physiology and/or row For data) process 501.Pre-processing with analytic process 500 includes for executing each selected data set including for example filtering The process 502 of signal processing including wave, channel removal, resampling etc..Pretreatment includes for storing with analytic process 500 The process 503 of data analysis time-histories from each selected data set.Pretreatment includes for calculating with analytic process 500 The process 504 of ERP (for example, MMN, P300 etc.).Pretreatment and analytic process 500 include for executing presently disclosed technology Statistical analysis and/or sorting technique are to provide vulnerability and/or the pathological evolution for nervous system or neuropsychiatric disorders Assessment process 505.Pretreatment and analytic process 500 include for reporting and/or presenting and nervous system or psychoneural The process for the information collection (e.g., including one or more quantitative values) of the selected anatomy category associations of obstacle assessment analyzed 506。

Fig. 6 shows exemplary pretreatment and analysis code (for example, with MATLAB Script Programming) using pseudocode Example.As shown in fig. 6, illustrative code to one or more data sets (for example, these data sets can include one or Multiple physiologic therapy situations, for example, ketamine (ketamine) and potential treatment) it is recycled.In this example, exemplary Pretreatment and analysis code every time only memory store up a data set, for example, to reduce memory and calculated load.? After data set has been processed and its related data has been extracted, it is released from memory and by subsequent number It is replaced according to collection.

The computer screen that Fig. 7 shows the exemplary graphical user (GUI) of illustrative Analysis of programming process is cut Figure.By using the exemplary interfaces, user can be readily selected them and wish to analyze which or which data set, and energy It is enough that there is the option for comparing data set between multiple physiologic therapies.For example, Left-Hand Panel is that EEG file search current path is arranged side by side Their own filename out.Using the panel, user is able to use their mouse to be highlighted where they want analysis A little data sets and they are selected by click " Select:treatment " button.This " will move selected filename It is dynamic " to the panel on right side, indicate which file they have selected for.User, which is then able to press " Next treatment ", to press Button is to select the data set of another physiologic therapy.They can equally press " Previous treatment " button, if They wish to return to and edit before selection.When pressing " Finish " button, program will start automated analysis process simultaneously And it will be terminated with being then able to the destination file being saved to user's output.

In order to show the exemplary system and method including the computer implemented data analysis program of custom design Performance and accuracy, illustrative implementation include the analysis method from custom design illustrative result with make With the comparison between the result of existing software package (for example, BrainVision Analyzer 2.0).

I.6. the MMN ERP characterization of the mankind

For example, the timing and determining for scalp pattern using the MMN component of the mankind characterize, illustrative result, which discloses, to be continued Time be about 56~190ms, peak amplitude at 104ms be -1.83 μ V (F (1,1259)=97.12；P=0.000) MMN ERP and volume-center and center scalp distribution.

Fig. 8 A and 8B are shown using the program of existing software tool (Fig. 8 A) and custom design (for example, using MATLAB script) (Fig. 8 B) carry out the illustrative ERP carried out according to illustrative MMN data set to human subjects and handle and analysis Result data graphs.Data and curves show the waveform from the human subjects for using Cz electrode channel.For example, figure The data and curves of 8A and 8B show the exemplary patterns of the MMN of Healthy People object.The data graphs of Fig. 8 A include standard And deviation waveform, and show the strong differentiation between standard and deviation, as shown by MMN, which is to be Deviation waveform subtracts the difference of reference waveform.Similarly, in the fig. 8b, using the illustrative of the program of illustrative custom design ERP processing has all obtained substantially the same result for the MMN waveform in expected time interval with data analysis.

I.7. the P300ERP characterization of the mankind

P300 is studied in the average response to low deviation and high deviation.For example, the timing of the P3 component using the mankind With the characterization that determines of skin pattern, it is about 208~256ms, peak value at 228ms that illustrative result, which discloses the duration, Amplitude is the P300ERP of 0.72 μ V (t=3.54, p=0.000).

Fig. 9 A and 9B are shown using the program of existing software tool (Fig. 9 A) and custom design (for example, using MATLAB script) (Fig. 9 B) carry out the illustrative ERP carried out according to exemplary P300 data set to human subjects and handle and analysis Result data graphs.Data and curves show the waveform from the human subjects for using Cz electrode channel.For example, figure The data and curves of 9A and 9B show the not figure by the P300ERP of the Healthy People object of physiologic therapy.For example, P300 It is the positive waveform for reflecting the reaction for deviation stimulation.Use existing software tool or the foot of illustrative custom design This calculated illustrative P300ERP is consistent, for example, showing the reliability of the program of illustrative custom design.

As described above, for assessing and psychoneural or the associated vulnerability of nervous system disorders and progress The method disclosed herein of venereal disease reason and the example implementations of system show curative effect and detect MMN's and P300ERP Other advantages, for example, the MMN and P300ERP is associated with the obstacle of such as schizophrenia and Alzheimer disease etc.This The implementation of technology disclosed in text is able to use improved or different specific stimulation and presents mode and EEG acquisition system " targeting " and the associated different ERP of other interested nervous systems and/or neuropsychiatric disorders.

Figure 10 show by user (for example, doctor or patient) implement for monitoring psychoneural and/or nerveous system The procedure chart for the liability of obstacle or the exemplary process of progressive pathology of uniting.In the schematic diagram of Figure 10, non-rectangle text Frame reflection program can inquire the possibility inquiry of user (for example, operator), exemplary to customize towards desired target Application.As shown, for example, operator can receive on how to by electrode cap or illustratively after opening program Frontal electrode sensing system is placed in the instruction on the head of object.Then, for example, can be presented to operator for starting to pierce Swash the instruction presented, these instructions equally can simultaneously or before it start data record with presenting for stimulation.User It will be notified that data acquisition and stimulation are presented when to have completed.The next part of exemplary process can require user to select He/her whether wish by the data collection session of current data collection session and precedence record and/or with normal healthy controls person's group Data be compared.For example, user can monitor the progressive pathology of patient by providing the option, and by the data With being compared for normal person.

The result of implementation from exemplary application can export one of in various formats.For example, result It can be exported with the format of " summarizing (Summary) " or " detailed (Detailed) ", described by example as shown in Figure 10 's.In illustrative summarized results format, it will provide the user with the user friendly or non-expert's type layout of analysis result. In certain examples of summarized results format, application can be based on the generated generated information collection in data analysis process And text description is exported, for example, " ability (function of normal threshold of feeling memory) of your detection error has declined ", " ... increase " or Person " remains unchanged ".For example, summarized results format can present quantitative result, for example, for rendered object to the easy of the obstacle The meeting of the score and statistical result (for example, p value) and their precedence records of illness or the obstacle progressive pathology The readable chart of words, the readability icon can allow for user to carry out visualizing monitor to the progress of their obstacle.In example Property detailed results format in, it will provide the user with analysis result more complicated layout.For example, in addition to illustratively summarizing knot Except fruit format, detailed results format is equally capable of providing ERP chart and landform voltage pattern (for example, wearing in user complete In the case where EEG cap).

II. for the treatment pharmacological agent to neuropsychiatric disorders in non-human primate object (biological model) Assessment the example implementations with MMN and P300ERP

II.1. structure is presented in illustrative stimulation

In the realization of the illustrative presently disclosed technology of the curative effect for assessing the treatment for neuropsychiatric disorders In mode, the bull macaque (rhesus macaque) for the use of two such as ages being 6 years old and 7 years old.All programs and animal care are all It checks and approves through Sol gram research institute animal care and using the committee, and is protected according to the experimental animal of national sanitary research institute It manages with guide for use and executes.

Illustrative stimulation present structure include in implementation process to being sitting in segregate, rather dark room Interior object presents the passive sense of hearing intensity oddball mode of the tone of varying strength.For example, auditory stimulation includes low intensive Or the pure sinusoid tone (for example, 1500Hz) of high-intensitive 100ms (for example, 10ms rise/fall).Frequently (standard) and very (deviation) stimulation occurred less accounts for for 80% and 20% time respectively, as shown in Figure 4.700ms is divided between stimulation.For example, 1200 standard stimulus and 300 deviation stimulations are presented in each recording conversation.For example, using high deviation (for example, low mark It is quasi-) and two kinds of situations of low deviation (for example, high standard), for example, for allowing under different backgrounds (for example, standard or deviation) Comparison to the reaction of identical stimulation (for example, low or high).

The illustrative stimulation presented for being used to control stimulation in this example presents mode and uses Cogent 2000 Programming.Tone is presented to illustrative non-human primate (NHP) object using amplifier and loudspeaker.In order to make to move It minimizes, NHP is trained so that it maintains center fixation.For example, fixation target is 21 using distance NHP object 40cm The CRT monitor of inch is presented in the red circle (for example, diameter is 1 degree) in black background.Target is presented in auditory stimulation Start before occur, and recording conversation it is entire period remain it is visible.For example, two methods be used to create it is exemplary Red center fixation point and the rectangular stimulation of blue.For illustrative fixation point, for example, computer implemented process (for example, Created using MATLAB script) be used to creation height and width be 350 pixels black background image (for example, red gun Equal to 0；Green rifle is equal to 0；0) blue rifle is equal to.Then, illustrative script runs nesting using round normal equation For circulation is to change into 0 for green rifle and blue rifle is changed into 0 for half by the way that the red gun of image is changed into 255 Diameter is that the pixel within 7 length in pixels changes into red.For the illustrative rectangular stimulation of blue, imaging software is used to create Image having a size of 157 × 157 pixels, the red gun of the image are equal to 0, and green rifle is equal to 0, and blue rifle is equal to 255.Show The red center fixation point of example property is used to help NHP object to maintain fixation in entire recording conversation.

Illustrative computer implemented process is used to the journal file of configuration display, Cogent 2000, parallel to hold Mouth and sound card.In addition, illustrative computer implemented process is used to auditory stimulation (for example, bass and high pitch) and vision Stimulation (for example, fixation point and blue are rectangular) is loaded into core buffer.In addition, in the illustrative reality using NHP object In existing mode, for example, illustrative process presents the stimulation of two or more deviations discontinuously to create biggish deviation Perception.For example, this is realized by creating presenting sequentially for array comprising " 1 " and " 2 ".For example, " 1 " indicate standard Stimulation, and " 2 " indicate deviation stimulation.In these implementations, for example, abovementioned steps can be held before stimulation is presented Row, to reduce calculated load and to increase delay precision.

For example, presented For circulation (the exemplary MATLAB script of illustrative computer implemented process, To generate fixation target) in, fixation point is presented and that NHP object is maintained as in entire block is visible.Then, the circulation along It presents sequence and repeats.When it encounters " 1 ", illustrative computer implemented process will be first by event flag/trigger It is sent to physiological data collection system (for example, EEG logger computer), followed by standard stimulus is presented (for example, right In situation 1 be bass；It is high pitch for situation 2).Similarly, when it encounters " 2 ", illustrative computer implemented process Event flag/trigger will be sent to illustrative EEG logger computer first, followed by deviation stimulation (for example, It is high pitch for situation 1；For situation 2 be bass) present.Which kind of stimulation event flag/trigger points out (for example, low Or high) presented.For example, after following each auditory stimulation closely being interval (ISI) between stimulation for 700ms.

Being trained by using the positive reinforcement of standard to NHP object makes it maintain center fixation.Accurate eyes Position control is necessary in these illustrative implementations.For example, fixation target is only used for helping to make eye movement The auxiliary of minimum, and just because of this, fixation is not quantized.

II.2. illustrative EEG data collection/record

For example, EEG scalp reading is acquired with using the Vision Recorder software of BrainAmpMR system.Have The NHP EEG cap in 22 channels of the illustrative custom design of AgCl electrode is developed and is used for non-human primate pair The data collection of elephant is (for example, be used for the PCB ribbon cable with 5k resistor of BrainCap-MR；BrainCap MR Box 1.2；The sintering ring electrode of the heavy lead of electric shock-prevention safety socket terminal and 120cm with 1.5mm).

Figure 11 shows the image and schematic diagram for showing the NHP EEG cap in 22 channels of exemplary customized design.In Figure 11 In show the image 1100 of illustrative NHP EEG cap, show detection cap EEG electrode exemplary layout forehead view Figure.Figure 11 also shows the top surface (signal of position of 22 electrodes for depicted example in illustrative NHP EEG cap Figure 112 1) and right side (schematic diagram 1122) explanatory view three-dimensional reconstruction schematic diagram 1120.Figure 11 is also shown for retouching Draw the schematic diagram 1110 of the two dimension view of the position of 22 electrodes in illustrative NHP EEG cap.The illustrative NHP EEG cap includes to be configured according to two-panel design for allowing the scalable material fitted closely on the scalp of monkey Material.For example, illustrative retractable material can include the elastic fabric material of medium wt.NHP EEG cap, which has, to be used for 22 channels of electrode density identical with the cap in 64 channels of the mankind are provided.The illustrative NHP EEG cap is designed to use In same group of AgCl electrode for being suitble to the BrainAmpMR system used in human subjects.For example, illustrative NHP EEG cap Such as non-human primate can be used to provide and be used for psychoneural and/or nervous system disorders for assessing The proper component of the exemplary system of the presently disclosed technology of potential treatment pharmacological agent.The illustrative NHP EEG Cap is capable of providing " full scalp covering " for non-human primate object, and providing includes that extensive data is for example allowed to receive Collection and integrated data collect both the advantages of interior, and with brain signal collected in human subjects it is direct compared with.It should The production of illustrative NHP EEG cap includes two semi-moon shaped block parts of cutting, the two block parts are then stitched together.So Afterwards, small plastic skin band or other fixing components are attached to each end to form chin strap.Finally, 22 electrodes are consolidated Determine device to be placed on cap, 22 electrodes pair shown in the schematic diagram 1110 and 1120 with Figure 11 in retractable material The specific position answered.

Illustrative EEG data collection technique for NHP object includes following preparation process.For example, (1) makes NHP head The position in portion keeps stablizing, for example, it is desired to which the head of rigidity is fixed, so MR compatibility headpin (head-post) is designed to use In on operation implantation dorsal skull.For example, (2) NHP EEG cap is placed.In the illustrative implementation, shown in Figure 11 Illustrative customization NHP EEG cap be used for macaque object.For example, (3) EEG constraint chair is used for illustrative NHP pairs As.For example, MR compatibility chair customized is designed using MR biocompatible material.NHP is by the position according to sphinx shape It sets and is constrained in chair, head process goes out, and it is stabilized, and forward-facing.For example, (4) there is the 3D scalp of electrode position to rebuild quilt Creation.For example, the 3D that the scalp of each animal is created using illustrative Polhemus Fastrak system is rebuild, Mei Ge electricity The accurate location of pole is all accurately positioned.This allows the creation of the topographic map of the voltage's distribiuting to EEG data collection collected.

NHP object is trained to what vision was fixed before physiological signal record.For example, illustrative computer implemented Process is developed, with training NHP object (for example, two scripts programmed on CORTEX) in terms of vision fixation.First The implementation of exemplary script includes the illustrative red center that the diameter of display on a dark background is measured by 1 degree of visual angle Fixation point.When NHP object, which watches the fixation point in the window at 4 ° × 4 ° visual angles attentively, reaches minimum 1000ms, object can receive small The reward (for example, award system from Crist instrument company) of cup fruit juice, is followed by the interval (ISI) between the stimulation of 0ms. For example, the ISCAN eye tracking system (ETL-200) for monitoring eye movement is used.The exemplary process is used to train Object fixates, and rapidly fixation point associates with reward.The implementation of second script further includes diameter The red center fixation point measured by 1 degree of visual angle.But for example, concurrently, the black and white of high contrast, which will be abstracted image, to be occurred 750ms is reached behind in fixation point, is followed by the ISI of the shake of 750~1000ms.For example, Script controlling 4 to 6 abstract images The flashing of series, and require object fixation during each image presentation.If NHP object is for each image presentation Keep fixation in the window at 4 ° × 4 ° visual angles placed in the middle about fixation point, then object will receive the reward of cuvette fruit juice, together When synchronize the rectangular stimulation for presenting the vision blue for the pause for being used to indicate reward and test bay.The rectangular stimulation of each blue Presented 1500ms, and followed by under a series of abstract graph pictures.

Trained and recording process includes: that NHP object is fixed on the compatible chair of illustrative MRI customized first. This both provides constraint for animal target or is provided for comfort.For example, chair is placed horizontally at for recording process It records on indoor desk.This allows NHP object in the position of sphinx towards presenting monitor and loudspeaker.So Afterwards, EEG cap is placed on the head of NHP object, and head is fixed on constraint chair.Then, the electrode gel of Signa makes Each base part used in cap is injected at curvilinear plastic injector, with the scalp of electronics itself and object it Between create conducting bridge.We equally carry out massage gel using wooden cotton swab, establish stronger conductance will pass through reduction impedance. Then, the door of recording room is finally closed, and lamp completely closes.During training is with record two, NHP object uses infrared phase Machine is monitored closely.

II.3. illustrative EEG data analysis

Illustrative EEG data is analyzed using software Analyzer 2.0.Illustrative EEG data analyzes program bag It includes: so that the data set from original record reference is quoted identical rear pillow part channel again first, as different plant species (example Such as, people: Oz, O1, O2, PO7, PO8, P7, P8；Macaque: Oz, O1, O2, P3, P4) between new comparable reference.This is followed by Bandpass filtering (for example, low cutoff frequency: 0.1Hz, higher cutoff frequency: 50Hz), and based on spline interpolation and by sample rate from 1000Hz changes into 250Hz.For example, in order to avoid derived from the analysis artefact of the difference of sample size, illustrative data set is first It is first segmented relative to deviation mark position (for example, starting: -1000ms terminates: 600ms), so that it will will include all partially Difference test (for example, N=300) and the only code test (for example, N=300) directly before deviation.Then, for example, institute The analysis time-histories of generation relative to deviation mark position or standard sign position (for example, starting: -200ms terminates: 600ms) into Row segmentation, to identify relevant deviation and standard analysis time-histories.For both standard and deviation analysis time-histories, base Line correction (for example, starting: -200ms terminates: 0ms) is applied, and multiple features artefact excludes tool and applied (for example, being applied to Whole channels；Maximum permissible voltage step: 50 μ V/ms；Maximum allowable interval value difference: 200 μ V；Minimum allowable interval activity: 0.5 μV).ERP (mean value) is then counted for each channel and situation (for example, high standard, substandard, high deviation and low deviation) It calculates.For example, difference wave (for example, deviation subtracts standard) is for two kinds of situations (for example, low deviation subtracts substandard and high deviation Subtract high standard) it is calculated, and then low and high difference wave is averaged to obtain MMN component, and for inclined The low reaction of difference and high reaction are averaged to obtain P3 component.

II.4. the identification of non-human primate ERP

In the illustrative implementation, illustrative MMN component and P3ERP component are known in the mankind first Not, and then the similar component in non-human primate is identified.For example, ERP component uses established use phase With test mode (oddball mode, in this mode MMN be deviation stimulation subtract standard stimulus difference wave and P3 inclined Be observed in poor irritant test) criterion identify, and for these illustrative ERP components determine timing, electrode position, The distribution of voltage scalp and neural generators.For example, being established near peak amplitude in average ERP wave after identifying MMN The when window of 40ms.Window is used to extract the peak amplitude values of each NHP object from single test when this is illustrative.Example Such as, these values are then used to that (for example, factor 1: standard is to deviation in the two-way duplicate measurements ANOVA for each species；Cause Plain 2: high to low) statistical analysis in.P3 component is studied in the average response to low deviation and high deviation.Similarly, example Such as, after the P3 component of the identification mankind and monkey, 40 milliseconds of when window is established near peak amplitude in ERP wave, and This when window be used to extract average amplitude value from single test.For example, the statistical significance of P3 reaction makes in each species It is calculated with t inspection.

II.5. it is analyzed using the exemplary EEG data of the program of custom design

For example, being similar to the liability or progress venereal disease for assessing nervous system or neuropsychiatric disorders of human subjects The example implementations of reason, MMN component and P300 component are using existing software package (for example, BrainVision Analyzer 2.0) and illustrative custom design computer implemented analytic process (for example, with MATLAB Script Programming ) calculate, to handle MMN the and P300 data from NHP object, to create ERP waveform.Illustrative program is implemented For automatic data processing (for example, signal processing step being executed, for example, filtering, channel removal, resampling etc.), MMN is calculated Difference wave ERP calculates P300ERP, and executes statistical analysis to data-oriented.

II.6. the mankind's and non-human primate MMN ERP characterization

For example, using the MMN component of the mankind timing and scalp pattern determine characterization and it is proposed by Epidural cavity The definition of NHP MMN caused by recording, MMN ERP are seen in two kinds of species.For example, the duration of MMN is about in macaque 48~120ms, the peak amplitude at 88ms are -1.62 μ V (F (Isosorbide-5-Nitrae 09)=11.17, p=0.000), and the head in center Skin distribution.

Figure 12 A and 12B are shown using the program of existing software tool (Figure 12 A) and custom design (for example, using MATLAB script) (Figure 12 B) illustrative ERP for being carried out according to illustrative MMN data set to NHP object is handled and analysis As a result data graphs.Data and curves show the wave from the non-human primate object for using Cz electrode channel Shape.For example, the data and curves of Figure 12 A and 12B show the not MMN by the non-human primate object of physiologic therapy Basic figure.Similar to the MMN reaction in human subjects, data graphs in fig. 12 include standard and deviation Waveform, and show the strong differentiation between standard and deviation, as shown by MMN, reflect deviation waveform and subtract Go the difference of reference waveform.Similarly, in Figure 12 B, using illustrative custom design program illustrative ERP processing with Data analysis has all obtained substantially the same result for the MMN waveform in expected time interval.

II.7. the mankind's and non-human primate P300ERP characterization

As MMN, P300 is defined using identified characterization, and to the average anti-of low deviation and high deviation It is studied in answering.As MMN, P3 component shows the consistency between species.For example, the duration is big in macaque About 104~248ms, the peak amplitude at 196ms are 3.5 μ V (t=10.36, p=0.000).Two kinds of species all present Center-top scalp distribution.

Figure 13 A and 13B are shown using the program of existing software tool (Figure 13 A) and custom design (for example, using MATLAB script) (Figure 13 B) according to illustrative P300 data set for not by the exemplary of the NHP object of physiologic therapy ERP processing and analysis result data graphs.Data and curves are shown from the inhuman spirit for using Cz electrode channel The waveform of long class animal target.For example, the P300 for being similar to human subjects reacts, for example, non-human primate object P300 is significant forward voltage current potential, reflects the reaction to deviation stimulation.Using existing software tool or illustratively The calculated illustrative P300ERP of the script of custom design is consistent in expected time interval, for example, showing The reliability of the program of the custom design of example property.

The implementation of aforementioned exemplary is shown in illustrative model of rhesus monkey (for example, MMN is related in P300) The identification of ERP and it compared with the same ERP of the mankind.More implementations of system and method disclosed herein are assessed Object is for using the physiological status of " symptom inducing agent " or potential " restoring inducing agent " (for example, potential therapeutic agent) to grasp The reaction of work, to generate temporary defect and to examine potential recovery using the exemplary NHP animal model.

II.8 is used to examine symptom inducing agent with the MMN and P300ERP of the NHP object under different physiological status The illustrative implementation of (ketamine) and physiological saline excipient

The example implementations of system and method disclosed herein are performed for using in for example following three kinds of physiology MMN in exemplary model of rhesus monkey and P300ERP under situation assess the effect of ketamine: (i) acute anesthetic ketamine It is transfused (for example, 1mg/Kg), (ii) physiological saline (excipient) infusion, and (iii) acute anesthetic ketamine are transfused 5 hours Afterwards.

As shown in Figure 14 A-15B, compared with excipient " physiological saline ", ketamine infusion leads to MMN, and (ketamine is to physiology Salt water (F (1,290)=4.47, p=0.035)) and P300 (ketamine is to physiological saline (F (1,301)=27.73, p= 0.000) amplitude of the two is substantially reduced.No longer significantly (MMN ketamine was to 5 hours after 5 hours for the infusion that acts on of ketamine Ketamine (F (Isosorbide-5-Nitrae 03)=7.97, p=0.005) afterwards；Ketamine after 5 hours to physiological saline (F (1,290)=0.20, P=0.652)；P3 ketamine is to the ketamine (F (Isosorbide-5-Nitrae 11)=44.34, p=0.000) after 5 hours；Ketamine after 5 hours To physiological saline (F (1,301)=0.06, p=0.803)).There is no significant delay difference to be observed.Altogether, these examples Property the result shows that nmda receptor antagonist ketamine can reduce significantly the amplitude of MMN and P3ERP component in macaque.

Figure 14 A and 14B are shown using the program of existing software tool (Figure 14 A) and custom design (for example, using MATLAB script) (Figure 14 B) according to exemplary MMN data set for different physiological status NHP object carry out it is exemplary ERP processing and analysis result data graphs.Data and curves are shown from the inhuman spirit for using Cz electrode channel The waveform of long class animal target.For example, the waveform in Figure 14 A and 14B reflect include such as ketamine, physiological saline/ Control and after 5 hours of ketamine including different physiologic therapies under non-human primate object MMN reaction.? Data and curves in Figure 14 A show the reduction of the MMN amplitude under ketamine treatment, for example, with physiological saline/compare When injection is compared.The reduction reflects the decaying of the reaction for deviation stimulation.More particularly, for example, the reduction of MMN advantageously Show that the object is had any problem in detection error stimulation aspect now.Functionally, this temporary function of showing sensory storage processing Obstacle, symptom are common in the patient with schizophrenia and other neuropsychiatric disorders.Moreover, for example, also showing, early To at least after having injected 5 hours, these symptoms have disappeared, and animal model (for example, non-human primate) is shown Complete recovery is gone out.Similarly, in fig. 14b, using the illustrative ERP processing of the program of illustrative custom design and number According to analysis, allows rapid automatized and " easy to use ", obtained substantially the same result.

Figure 15 A and 15B are shown using the program of existing software tool (Figure 15 A) and custom design (for example, using MATLAB script) (Figure 15 B) according to illustrative P300 data set for different physiological status NHP object carry out example Property ERP processing and analysis result data graphs.Data and curves are shown from using the inhuman of Cz electrode channel The waveform of primate subjects.For example, it is including such as ketamine, physiology salt that the waveform in Figure 15 A and 15B, which reflects, The P300 reaction of the non-human primate object under different physiologic therapies including behind 5 hours of water/control and ketamine.Such as Be shown respectively compared with software and the exemplary process in Figure 15 A and 15B, ketamine treatment under (for example, with life When reason salt water/control injection is compared), P300 amplitude, which exists, to be reduced, and which reflects the decaying of the reaction stimulated for deviation.As In the example using MMN ERP like that, functionally, this shows that their attention is being redirected to deviation by these objects Dysfunction in terms of the ability of stimulation, for example, the dysfunction can be with schizophrenia and other psychoneurals or mind It is associated with through system disorders.As shown by the waveform of the data graphs of Figure 15 A and 15B, early arrive at least is being injected 5 hours Afterwards, these symptoms have disappeared, and animal model (non-human primate) illustrates complete recovery.

As described above, for being assessed using non-human primate biological model for nervous system or mind The method disclosed herein of potential treatment pharmacological agent through phrenoblabia and the example implementations of system, show Curative effect and for detect with the associated physiological reaction of such obstacle (for example, MMN and P300ERP) and inspection for In animal model induce " desired " physiological status different material and its about these neural markers modulation other Advantage.

Figure 16 show for allow user (such as by non-human primate be used as animal model cological drugs study Personnel) come the procedure chart for the exemplary process implemented, for assessing potential treatment pharmacology agents on neural system or nerve The curative effect of phrenoblabia.In the schematic diagram of Figure 16, non-rectangle text box reflection program can inquire user (for example, operation Member) possibility inquiry, to customize illustrative application towards desired target.As shown, for example, open program it Afterwards, the instruction that operator can receive on how to be placed in cap on the head of object (for example, non-human primate).With Interested drug is injected for them are indicated in family, and formulating it is " symptom induction " or " restoring to induce " medicine Agent.The example of symptom induction drug can include the ketamine of the Subanesthetic dose as nmda receptor antagonist.Restore to induce Drug can be such as researcher to the arbitrary target drug of mitigation or the inspection for curing neuropsychiatric disorders.One kind can The situation of energy is use while symptom induces drug and restores to induce both drugs.For example, researcher can result in temporarily Feeling and/or cognitive defect (for example, reduction of MMN and P300 amplitude), be followed by via drug target and induce recovery.It is logical Cross and do so, user will test-target drug for nmda receptor antagonist (for example, ketamine) influence (simulation disease Disease) curative effect.

After injection, for example, can be presented to operator for start stimulation present instruction (e.g., including selection cut open Analyse classification), these instructions can also start data record while stimulation is presented or before it.User will be notified that number It presents and when has completed according to acquisition and stimulation.The next part of exemplary process can require user to specify whether he/her wishes Hope by current data collection session and the data collection session (for example, the treatment recorded before) recorded before and/or with it is strong Health control group data are compared.

The result of implementation from exemplary application can export one of in various formats.For example, result It can be exported with the format of " summarizing " or " detailed ", illustrated by the example as shown in Figure 16.Illustratively summarizing As a result in format, it will provide the user with the user friendly layout of the non-expert of analysis result.In certain of summarized results format In a little examples, application can export text description, example based on the generated generated information collection in data analysis process Such as, " drug target has improved the ability of detection error ".For example, summarized results format can present quantitative result, such as For describing the score of the rank of the pathology of nervous system or neuropsychiatric disorders.Moreover, for example, summarized results format can be given User presents the statistics p value of the comparison of standard and deviation.In illustrative detailed results format, it will provide the user with analysis As a result more complicated layout.For example, detailed results format is equally capable of providing other than illustrative summarized results format ERP chart and landform voltage pattern.

Instruct sorting technique

In certain aspects, for example, presently disclosed technology includes the system and method for data and signal processing, packet It includes and realizes classifier, test statistics and the machine learning algorithm of the analysis to collected physiological data.In itself, example Such as, EEG data is usually noisy due to electrical interference, muscle activity, direct current (DC) offset, sweat and other factors.This Kind undesirable signal-to-noise ratio (SNR) results in the need for usually collecting data via a large amount of test, allows to acquire to being studied The sufficiently large sample size that is accurately detected of effect.Presently disclosed technology includes that can be applied to EEG or other lifes Reason signal data analysis so as to reduce significantly test necessary amount (for example, thus reducing Check-Out Time) sorting algorithm with And customization test statistics.

Examples described herein classification method is made in classification method using identifiable cognition and physiological parameter Related features, to be inferred to brain states and relevant potential pathology according to nerve signal.These features are related to Such as interested specific electrode and it is specific when window, for example, wherein known ERP show it is relevant to controlled stimulation and Its statistic can with morbid state, the liability of disease and/or pharmacological agent there are the fluctuations that one changes.For example, After stimulation is provided and collects statistical information, it can generate for providing the example for nervous system or neuropsychiatric disorders Property treatment (for example, pharmacological agent) the value of effect degree, the seriousness of obstacle or object vulnerable to obstacle effect It dissects.

Classification whether with another assume compared with one hypothesis background under, illustratively instruct the reality of sorting technique Example pretreatment stage is as follows.The related electrode (for example, EEG scalp electrode) for identifying physiological data collection module is related to stimulation Type or type.For example, the identification can include by the EEG signal number in the specific test k in time storehouse t under condition c According to being expressed as y [c, k, t].For example, condition is in specific nervous system or neuropsychiatric disorders (for example, schizophrenia) background Under can include object of the physiological saline to ketamine or health objects to easily ill.By (y [c, k, t]: k=1 ..., K) It averages for k, to create y [c, t].The null hypothesis of one core is, such as: H0 (null hypothesis): y [1, t] statistic Statistic with y [2, t] is identical；H1 (alternative hypothesis): y [1, t] statistic and the statistic of y [2, t] are not identical 's.

For example, data can be primarily based on " training " mode to be divided into known classification, example using the method being subjected to supervision Such as, wherein pharmacological agent is clear to the degree that brain states impact.For example, physiological saline is a pole End, however the pharmacological agent of high dose is that another is extreme.In this way, data set can be examined to understand pharmacology medicine The effect of agent, for example, characterizing pharmacological agent by using regression analysis is influencing the journey of interested brain states The successive value of degree.For example, event related potential it is interested when window can be based on related to interested specific brain mark Known Cognitive Neuroscience and neurology preassign.

For example, not using training data in the setting not being subjected to supervision.On the contrary, for example, this is considered as by we wherein deposits In a series of composite hypothesis check problem of possible parameters.For this quasi-mode, for example, natural assumption is (in test of normality Therewith occur after) be y [1, t]-y [2, t] be normal state.Thus, under null hypothesis, the difference have 0 mean value and Unknown variance.Under alternative hypothesis, there is difference Non-zero Mean and unknown variance (to be not necessarily and the variance at H0 Identical variance).

Because be in the variance under H0 and the mean variance at H1 it is unknown, this is that composite hypothesis is examined Problem: all there are many distributions under each hypothesis.The grouping for being related to the classifier of composite hypothesis inspection not being subjected to supervision can be by It realizes, these classifiers are all theoretically reasonable in different ways under different hypothesis.For example, examining system Metering can be developed, which is the function of observed data.According to the test statistics, p value can be by It calculates or is estimated, which is compared with threshold value (for example, 0.05).If it is more than 0.05, null hypothesis is received； Otherwise refuse null hypothesis.

Test statistics can include from such as normalization maximum likelihood and/or standard statistical routines (for example, ANOVA F score value) method, based on estimated mean value and variance.

After calculating test statistics, at least inspection extremely as the test statistics observed before is observed The likelihood for testing statistic is calculated under null hypothesis.Because null hypothesis has unknown variance, this is a compound vacation If check problem, and none specific natural way calculates p value.For example, multiple modes can be developed use In estimation p value.One example includes: to execute parameterized procedure to assess probability expression to use the estimation of P0, it is assumed that is had According to the normal distribution of the variance of data estimation.If the distribution g (d) of test statistics is according to closed form at H0 (for example, For t, Z, F, the ANOVA inspection) known, then be able to carry out and directly calculate or be able to use look-up table.

For example, if can be realized Monte Carlo using more complicated test statistics (for example, normalization likelihood ratio) (Monte Carlo) method carrys out estimated probability.For example, nonparametric Bootload can be estimated to normalize the p of maximum likelihood situation Value.Aforesaid class device mentioned above provides statistical information (for example, p value in the case where not being subjected to supervision).This can lead to It crosses the function used and is converted into serious " degree " being monotonically changed in the classification with confidence level.For example, natural mistake Journey is to distribute confidence level " log loss " for negative logarithm based on probability.

For stimulate automatically present, data acquisition and data processing illustrative methods solution

In certain implementations of system and method disclosed herein, for example, computer network and analytical technology by with It draws, records and processing/analysis MMN and P300ERP component.The availability and speed of the system are improved, it is disclosed herein Exemplary " full-enclosed " application system of technology can be implemented to automatically stimulate present, data acquisition and data processing.It is logical It crosses and these features is integrated in a related system, time needed for data processing efficiently and accurately, space and availability It is optimized.In an example, illustrative " full-enclosed " application can be implemented in computer system, and be used Qt, " cross-platform and UI frame " (Qt Developer Network) configure, dependent on presently disclosed technology it is illustrative simultaneously Assassinate swash present, data acquisition and signal processing model.Illustratively " full-enclosed " application system is equally able to use other volumes Cheng Yuyan (for example, Java) Lai Shixian, so as in conventional computer system (for example, laptop computer and server etc.) And the program is established on mobile device (for example, smart phone and tablet computer etc.).

In the example of Qt, exploitation is structured to become extensive basis.Particularly, for example, being illustratively based on Qt " full-enclosed " program can present various stimulus modalities (e.g., including two kinds of vision and the sense of hearing), record hardware from various EEG Upper acquisition data, and realize different analytical technology and step.On a large scale, for example, system from open data thread to adopt Online EEG data of the collection from specific source starts.In the specific example, multiple Application Programming Interface (API), example are used Such as, to allow to put using from including such as Brain Products EEG system, Neurosky Mindset equipment, AD8224 Data are acquired in various equipment including big device, TGAM1 amplifier and epidermis electronic system.Meanwhile selected stimulus modality (example Such as, sense of hearing oddball sequence) it can be activated and be presented to object.Stimulation, which is presented, to be able to use with data acquisition in same machine Multiple computer processors in device are concurrently run.They equally can mutually convey information, for example, stimulation is in what when Between point present.By conveying such information, subsequent signal processing can have about " wherein " and " at what When " specifying informations of the relevant data of relevant and event occurs.In Qt, (s) signal processing module is configured for simply Ground " calling " to be applied to data one or more processing/analytic functions.By doing so, for example, in signal processing technology Aspect allows extensive adaptability.As a result, a possible example can include allowing experienced user by his/her letter Number processing script " upload " to proposed using upper.But in order to increase availability, illustrative application can equally be matched It sets for being supplied together with " built-in " signal processing technology, for example, the data of illustrative custom design described above It analyzes program (for example, using MATLAB script) and instructs classifier.

The example of " full-enclosed " program based on Qt is described, which includes following item.Illustratively based on Qt's Under the background of " full-enclosed " program, term " user " can refer to the operator of application；" object " can refer to its data Just collected individual；" stimulation " can refer to any one example for the stimulation presented to object；" test " can refer to The entire sequence for the stimulation presented before handling data to object；" polymorphism " can refer to that same programing function is relating to And the situation that may be differently carried out for example, by different construction classes (build classes) when different background；And " virtual function " can refer to the function being differently implemented in the different subclasses of superclass.

" full-enclosed " application system includes presenting and the client-server of data processing module containing data acquisition, stimulation Device solution.For example, client and server be located at can reside at identical or isolated machine (for example, local and/or On two different frames in remotely).Client, which contains data acquisition, presents module with stimulation, and servers host data Processing module.By carrying out structuring, " full-enclosed " application system energy to client-server solution in this manner It is enough to have for the adaptability in numerous equipment.For example, typical mobile device (for example, smart phone or tablet computer) is usual Without the computing capability, speed and battery life for handling and analyzing mass data (for example, EEG data).In the example In disposition shape, " full-enclosed " application system can be resided on two individual machines.For example, stimulation is presented and data acquisition module Block can reside in mobile device itself, and signal processing module can reside on remote server.The long-range signal Processing module can be received via internet (for example, Wi-Fi and/or cellular data network) and returned data.Pass through distribution Various modules, " full-enclosed " application system can be used for mobile device according to efficient and available mode.On the other hand, If the computer (for example, on knee or desktop computer) of individual Internet access routine, they will be in local use Using wherein module (for example, stimulation is presented, data signal sampling and processing) can reside in uniform machinery.This is for example It can be optimal that individual, which does not have in the situation that reliable linking Internet connects,.

Figure 17 shows the schematic diagrames of the example for the general architecture for showing illustrative " full-enclosed " application system.? In schematic diagram exemplary big box (for example, be designated as " StimulusGrid ", " DataThread " and " DataAcquisitionModule ") it is the core classes applied.Lesser green frame pair in illustrative core classes box It should be in the various functions of each class.Red side label represents the Qt signal emitted from a class to another class (for example, " clicked () ", " beginStimulus () ", " stimulusDone () ", " trialDone () " and " timeout () ").Black surround mark Label represent may occur cause subsequent function called various events (for example, " Start Timer (starting timer) ", " reset (reset) ", " Stimulus Condition Reached (incentive condition reaches) ", " Stop Timer (stops timing Device) " and " Connection Successful (successful connection) ")." Run Button (operation button) " box is represented in example Reality " Run (operation) " button on the graphic user interface of property.

In the illustrative frame, for example, defining two classes of two nucleus modules for representing client operation: StimulusGrid and DataThread.One additional class, data acquisition module are instantiated in DataThread module It is interior.These modules are instantiated in the communication connection for creating the two cross-threads and create the main window of graphic user interface (MainWindow) in thread.

Data thread class is the subclass of the QThread class of Qt, and it is same together with the main thread that Qt is applied which is designed to Shi Yunhang.To, such will instantiate DataAcquisitionModule, for from different data acquisition hardwares Interface connection.For this purpose, DataAcquisitionModule class is able to carry out subclass subdivision to promote and different hardware The communication of equipment.It is existing in DataAcquisitionModule class two virtual functions (openConnection () and GetData ()) it specified should be implemented in subclass for reflecting the function interacted with the dedicated hardware of equipment room.This is provided Generation of whole hardware device interfaces by the use of class polymorphism on the main thread of execution, this allow that application depends on The simple and effective extension of the data acquisition ability of hardware.

StimulusGrid class represents the stimulus modality that will be presented on main thread to object.The example of this class will be with Function is presented in the stimulation that DataAcquisitionModule runs them simultaneously together.This class is able to carry out subclass subdivision, with By allowing main thread that the generalization that polymorphism is used for stimulus structure is allowed stimulus modality (for example, sense of hearing oddball) It fast implements and integrates.Illustrative framework has made the function modoularization of two core classes.Module interface defined above Control is provided via the interaction between class, and allows each individual class function in the case where not influencing the function of other classes Extension/modification of implementation.This allows the rapidly and effectively expansion of StimulusGrid and DataAcquisitionModule Exhibition.

Exemplary codes

Class: StimulusGrid

Virtual void StimulusGrid::runGrid (): what execution must be completed before stimulation cycle starts The arbitrary initial of StimulusGrid configures.Executing in the function for task may include: that storage is specified on GUI by user Configuration Values, sequence of the initialization containing the stimulation presented to object or the initial frame of stimulation cycle is drawn on figure circle The array in face.

Virtual void StimulusGrid::startStimulus (): start to test.For can be with every x milliseconds just Duplicate period sexual stimulus, the function can initialize timing mechanism, for example, the example of the QTimer of Qt.The function is given SelectStimulus () function signals to start to call directly it or call it by timing mechanism.

virtual void StimulusGrid::selectStimulus(): selection is next to present to individual Stimulation.The function dynamically or by repeating pre-determined stimulus sequence to be presented selects to stimulate.It is desirable that for example, the letter Number should only execute the latter, because dynamically specifying stimulation (for example, calling random number for each iteration at runtime Device or the catalogue for dynamically searching image) it will affect time sequence precision.The function is generally tested all every time by called many It is secondary, because it is responsible for presenting for stimulation.Will equally DataThread::timeStamp () be given to each calling of the function It signals, to point out current packet number in the original data stream in timestamp QList, and points out to select in mark QList Surely the mark stimulated.

Virtual void StimulusGrid::stopStimulus (): the function will test complete when (for example, When having presented the stimulation of scheduled maximum limitation, or when timing mechanism has expired) it is called.It will stop with The associated any initialized timer of stimulation cycle, and then will give DataThread::stopAcquiringData () signals, to stop data acquisition.

Class: DataThread

Int DataThread::startConnection (): the function attempt via with The interface of DataQcquisitionModule::openConnection () and specified device hardware establish connection.In success Connection when being established, it will return to 0, otherwise return to -1.

Void DataThread::run (): in QThread, run () function is designated as staying in QThread object The concurrent function run when being derived for concurrently executing.Under the background of the application, it via Interface at DataQcquisitionModule::getData () is according to specified sample rate repeated acquisition data.Initial StimulusGrid::startStimulus () is equally given to signal to start stimulation cycle when calling.

Void DataThread::timeStamp (): pointing out the current location in original data stream, to make to be adopted The data sample of collection is associated with the specific example for the stimulation presented.Whenever new stimulation is via StimulusGrid:: SelectStimulus () is come when presenting to object, the function is all called.

Void DataThread::stopAcquiringData (): function tune when testing completion by stimulation thread With.The function discharges any hardware connection, and initialization counter is prepared again with testing for next time.It is also called ConnectServer () function.

Void DataThread::connectServer (): the function is connected to Local or Remote via socket port Server module.After a successful connection, the QList object containing mark, timestamp and data is resolvable to individual byte, And it is sent to code server.The function is called by DataThread::stopAcquiringData.

Class: DataQcquisitionModule

Virtual void DataQcquisitionModule::openConnection (): attempt to be opened to specified The connection of acquisition hardware.The function by containing specific to hardware interface code, for being communicated with to locking equipment.

Virtual int DataQcquisitionModule::getData (): from the biography of specified data acquisition hardware Enter one data point of reading in data flow.The function by containing specific to hardware interface code, for being communicated with to locking equipment And from wherein reading data.

The implementation of theme and feature operation described in patent document can following list realize: each germline System, Fundamental Digital Circuit or computer software, firmware or hardware, including structure disclosed in this specification and they Structural equivalents or combination that they one or more of work as are realized.The realization side of theme described in this specification Formula can be implemented as one or more computer program products, that is, be encoded in tangible and nonvolatile computer-readable One or more modules of computer program instructions on medium, for being executed by data processing equipment or for controlling data The operation of processing unit.Computer-readable medium can be machine readable storage device, machine readable storage carrier, memory set Material composition that is standby, realizing machine readable transmitting signal or the combination that they one or more of work as.Term " data Processing unit " covers all devices, equipment and the machine for handling data, including such as programmable processor, computer or The multiple processors of person or computer.In addition to hardware, these devices can also include for for discuss in computer program Create performing environment code, for example, for constitute processor firmware, protocol stack, data base management system, operating system or The combined code that they one or more of work as.

Computer program (also referred to as program, software, software application, script or code) can be with any form of programming language Speech is to write, including compiler language or interpretative code, and it can be disposed according to arbitrary form, including as independent journey Sequence or module, component, subprogram are suitable for other units used in a computing environment.Computer program is not necessarily Corresponding to the file in file system.Program can be stored in the file for saving other programs or data (for example, being stored in One or more scripts in marking language document) a part in, in be exclusively used in discuss in program single file in, or Person is in multiple mutually coordinated files (for example, file for storing one or more modules, subprogram or partial code). Computer program can be deployed as in a computer or be located at one place or be distributed in multiple places and pass through logical Communication network executes in the multiple stage computers that interconnect.

Process and logic flow described in this specification can be executed by one or more programmable processors, these Processor executes one or more computer programs to execute function by being operated to input data and producing output.This A little processes and logic flow equally can be by dedicated logic circuits (for example, FPGA (field programmable gate array) or ASIC are (dedicated Integrated circuit)) Lai Zhihang, and device can equally be implemented as dedicated logic circuit.

The processor for being adapted for carrying out computer program includes, for example, general and special microprocessor and any type Any one or more processors of digital computer.Generally, processor will receive and come from read-only memory or arbitrary access The instruction and data of memory or both.The primary element of computer is processor for executing instruction and refers to for storing It enables and the one or more of data stores equipment.Generally, computer will also include one or more for storing data big Capacity storage device (for example, disk, magneto-optic disk or CD), or be operationally coupled for receiving from these large capacities Store the data of equipment or transfer data to them, or both.But computer is not necessarily intended to have such set It is standby.The computer-readable medium for being suitable for storing computer program instructions and data includes the non-volatile memories of form of ownership Device, medium and storage equipment, including such as semiconductor memory apparatus, for example, EPROM, EEPROM and flash memory.Processor and storage Device can be aided with dedicated logic circuit, or be incorporated into dedicated logic circuit.

Although patent document contains there are many details, these details and be understood not to the scope of the present invention or The limitation of person's scope of the claims, but should be used as can be specific to the description of the feature of the specific embodiment of particular aspects.? The certain features described under the background of individual embodiment in patent document, which can equally combine, is implemented in single reality It applies in example.On the contrary, the various features described in the context of a single embodiment equally can individually be implemented in multiple implementations In example or it is implemented in any appropriate sub-portfolio.Moreover, although feature can be described as be in certain combinations above It works, or even initially as statement, but in some cases can from the combined one or more features stated Enough combinations deleted, and stated from the combination can be directed toward the modification of sub-portfolio or sub-portfolio.

Similarly, it is described in particular order in the accompanying drawings although operating, this is understood not to require This generic operation perhaps must be executed according to continuous sequence or be required shown by whole according to shown particular order Operation will be performed, to obtain desired result.Moreover, the various systems in patent document described embodiment The separation of component is understood not to require such separation in all embodiments.

Only describe a small number of implementations and example herein, and can be based in described and illustrated in patent document Hold to obtain other implementations, enhancing and variation.

Claims

1. it is a kind of for assessing the portable system of nervous system disorders or neuropsychiatric disorders, include:

Sending device is stimulated, for generating the stimulus sequence presented to object, wherein the stimulation includes vision, the sense of hearing or tactile Stimulate at least one of medium；

Sensor device, connect with the object interface with before and after, during the presenting of the stimulus sequence detection by The electroencephalogram EEG signal that the object is shown, the stimulus sequence are based on instruction and hinder with nervous system disorders or psychoneural Cognition-feeling of the one or more aspects of associated cognition or sensory function is hindered to dissect classification, wherein sensor device includes Three sensor electrodes on flexible base board, the flexible base board and with the sensor electrode telecommunication and in the flexibility Transmitter unit on substrate, wherein the sensor device is configured as one or more on the scalp for being worn on the object A wearable patch is to record electroencephalogram EEG signal and transmit recorded EEG signal, wherein three sensor electrode packets The grounding electrode of recording electrode, reference electrode and configuration between recording electrode and reference electrode is included, wherein three sensings Device electrode is aligned in the forehead area of object with sagittal direction；

Data processing system is communicated with the sensor device to receive transmitted EEG signal, wherein data processing system packet Containing one or more storage units and processing is configured as the electroencephalogram EEG signal of physiological data includes to generate The one or more processors of the information collection of one or more quantitative values of category associations are dissected with the cognition-feeling, it is described One or more quantitative values include describe the nervous system disorders or neuropsychiatric disorders of the object liability or into The quantitative score of the rank of row venereal disease reason；And

Brain-computer interface module is communicated with the data processing system and the stimulation sending device to be based on and information generated The data for collecting associated or therefrom obtaining are adaptively modified during the stimulation is presented to the object for institute The stimulus sequence of at least one of vision, the sense of hearing or haptic stimulus medium of individual subject is stated,

Its moderate stimulation sending device, data processing system and brain-computer interface module are being the single of smart phone or tablet computer It calculates and is realized in equipment.

2. system according to claim 1, wherein the brain-computer interface module be configured as based on it is described recognize-feel cut open Classification is analysed to determine the stimulus sequence that be presented to the object.

3. system according to claim 2, wherein the brain-computer interface module is configured as receiving and information generated The data for collecting associated or therefrom obtaining, and be configured as presenting the stimulation sequence for the object personalization The management of the relevant treatment of nervous system disorders or neuropsychiatric disorders to the object is modified during column.

4. system according to claim 1, wherein the smart phone or tablet computer include display screen and loudspeaker, The stimulation sending device generates image sequence respectively and generates sound sequence on display screen and loudspeaker.

5. system according to claim 1, wherein the stimulation sending device includes for generating haptic stimulus sequence Driver.

6. system according to claim 1, wherein the nervous system disorders or neuropsychiatric disorders include attention deficit Mostly dynamic obstacle (ADHD), autism spectrum disorder (ASD), Alzheimer disease, dementia, depression, bipolar disorder, spirit At least one of Split disease, epilepsy, multiple sclerosis (MS), Parkinson's disease, Huntington disease.

7. system according to claim 1, wherein the quantitative score is depicted in and the EEG signal of the object Acquire the rank on corresponding specific time.

8. system according to claim 1, wherein one or more of aspects of cognition or sensory function include paying attention to Power, memory, learning ability, fabricate characteristic, figure integration ability, semantic integration ability, target acquisition ability, mood valence, partially At least one of good or state of consciousness.

9. system according to claim 1, wherein the object during the detection of the EEG signal of the object just Undergoing the treatment to the nervous system disorders or neuropsychiatric disorders.

10. system according to claim 9, wherein the data processing system be configured as handling the physiological data with The information collection is generated, classification is dissected with the cognition-feeling with the curative effect comprising indicating the treatment to the object Associated one or more quantitative values.

11. system according to claim 10, wherein the treatment includes pharmacological agent, electro-shock therapy, cognition health At least one of multiple treatment or operative treatment.

12. system according to claim 11, wherein the data processing system is configured as based on information generated Collection is to generate machine program, and wherein the machine program drives another equipment or system and generated with managing from being contained in Information collection in information in the treatment that obtains.

13. system according to claim 1, wherein the sensor device includes for capturing the fortune for indicating the object The imaging device of the image of the dynamic or mobile object.

14. system according to claim 13, wherein the imaging device captures the eye movement of the object.